Compounds for the treatment of respiratory diseases

Abstract

The present invention relates to novel compounds, preparation of the compounds, and compositions comprising the compounds that are useful in the prevention or treatment of respiratory diseases such as asthma. The present invention also relates to the use of the compounds and compositions comprising the compounds in the treatment or prevention of respiratory diseases. [Selection diagram] None

Description

[Technology Field]

[0001] This application claims priority to Australian Provisional Patent Applications No. 2017901611 and No. 2017901647, the entire contents of which are incorporated herein by reference.

[0002] This invention provides imidazole compounds that show potential in the treatment of asthma and related conditions. [Background technology]

[0003] Asthma is a syndrome encompassing various different types of diseases with varying degrees of severity, causes, and triggers. The general characteristics of asthma syndrome are reversible airway obstruction, airway hyperresponsiveness, and airway inflammation, with the most prominent feature being the infiltration of the airway walls by eosinophils and T lymphocytes, in addition to mast cell activation.

[0004] Current asthma drug therapies include short-acting and long-acting β2-adrenergic receptor selective agonists (SABAs and LABAs) and inhaled corticosteroids (ICS). Ultra-LABAs are also currently available. Short-acting and long-acting muscarinic receptor antagonists (SAMAs and LAMAs) are usually used in combination with other bronchodilators and anti-inflammatory drugs, particularly ICS, for some patients. Leukotriene receptor antagonists (LTRAs) may also be added to different treatment regimens. Very recently, mepolizumab, a monoclonal antibody that neutralizes the efficacy of interleukin-5, a chemoattractant for eosinophils, has been shown to have an additional benefit to the combination of ICS and LABA in selected patients. However, especially in severe asthma, patients still exhibit symptoms and have periodic exacerbations of the disease. There is a considerable unmet need for drug treatment in severe asthma. These asthma exacerbations are thought to be caused in the majority of cases by respiratory viral infections of the lower respiratory tract. The viruses that cause these exacerbations include respiratory multinuclear viruses, influenza viruses, and rhinoviruses, which infect the respiratory epithelium. The epithelium of individuals with asthma is thought to be particularly susceptible to such infections and is associated with the worsening of the inflammatory response.

[0005] Studies have shown that TGF-β can impair the effectiveness of inspiratory corticosteroids (ICS). Furthermore, the inventors demonstrated that viral infection of the airway epithelium impairs ICS activity by inducing TGF-β activity. Drug targets of TGF-β carry the risk of autoimmunity and mitral valve defects. Surprisingly, the inventors identified casein kinase 1δ / ε, using compound PF670462 (International Publication No. 2016 / 149756), as a mediator of TGF-β-induced ICS insensitivity and demonstrated the usefulness of this agent in reversing steroid insensitivity.

[0006] A novel compound that can treat respiratory diseases, can be administered to the lungs, and exhibits reduced systemic effects compared to current drug therapies would be desirable. [Overview of the project] [Means for solving the problem]

[0007] The inventors identified a series of CK1δ / ε inhibitors designed to achieve increased LogP compared to PF670462. Increased LogP is strongly associated with increased lung residence time and is therefore strongly associated with longer dosing intervals for inhaled medications, often allowing for twice-daily or once-daily administration while minimizing systemic exposure. Overall, and surprisingly, this series showed similar activity to PF670462 in asthma-related assays.

[0008] These results are surprising, as is well known to those skilled in the art, because it is impossible to predict the effect of significant differences in the physical properties between the active compound and its analogues on the activity.

[0009] Furthermore, the N-methyl analog has been shown to be more potent than PF670462, maintaining a broad range of activity, including the ability to prevent TGFβ-induced ICS nonreactivity and the suppression of TGF-β and TNF-α-induced fibrogenic and pro-inflammatory growth factors and cytokines.

[0010] Therefore, in one embodiment, the present invention relates to a compound of formula (I):

[0011] [Formula 1]

[0012] (In the formula: R1 and R2 are (i) H, C 1〜6 Alkyl, C 2〜6 Alkinyl, C1 alkylC6 aryl, C6 aryl, C 3〜6 Cycloalkyl, and C 3〜5 They are independently selected from the group consisting of heterocyclines; or (ii) R1 and R2, together with the nitrogen atom to which they are bonded, form a heterocyclyl or heteroaryl group; R3 consists of F, Cl, Br, I, CH3, OCH3, OCF2H, OCF3, CO2H, and CO2C1〜10 selected from the group consisting of alkyl; R4 is C 0〜3 alkyl C 3〜12 cycloalkyl, C 1〜12 alkyl, C 1〜10 alkyl C6 aryl, C 1〜6 alkyl OC 1〜6 alkyl C6 aryl, C 0〜6 alkyl heteroaryl, and C 0〜6 selected from the group consisting of alkyl heterocyclyl; wherein each of R1, R2, R3, and R4 is optionally substituted) or a salt, solvate, enantiomer, prodrug, or polymorph thereof is provided.

[0013] The present invention relates to formula (Ia):

[0014]

Chemical formula 2

[0015] (wherein: R1 and R2 are (i) H, C 1〜6 alkyl, C 2〜6 alkynyl, C6 aryl, and C 3〜5 each independently selected from the group consisting of heterocyclyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclyl group; R3 is selected from the group consisting of F, Cl, Br, I and CH3; R4 is C 0〜3 alkyl C 3〜12 cycloalkyl, C 1〜12 alkyl, and C 0〜6 selected from the group consisting of alkyl heterocyclyl; wherein each of R1, R2, R3, and R4 is optionally substituted) or a salt, solvate, prodrug, or polymorph thereof is also provided.

[0016] In another embodiment, a method is provided for treating or preventing a respiratory disease in a subject requiring treatment or prevention of the respiratory disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby treating or preventing the respiratory disease of the subject.

[0017] In another embodiment, a method is provided for treating or preventing a respiratory disease in a subject requiring treatment or prevention of the respiratory disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby treating or preventing the respiratory disease of the subject.

[0018] Further provided are compounds of formula (I) or salts, solvates, prodrugs, or polymorphs thereof for use in the treatment or prevention of target respiratory diseases.

[0019] Further provided are compounds of formula (Ia) or their salts, solvates, prodrugs, or polymorphs for use in the treatment or prevention of target respiratory diseases.

[0020] Respiratory diseases may be selected from asthma, chronic obstructive pulmonary disease, interstitial lung disease (such as idiopathic pulmonary fibrosis) and other conditions associated with tissue remodeling, primary or secondary lung tumors, hay fever, chronic and acute sinusitis, and chronic and acute viral, fungal, and bacterial infections of the respiratory tract.

[0021] In another embodiment, a method is provided for improving the respiratory function of a subject requiring improvement of respiratory function, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby improving the subject's respiratory function.

[0022] In another embodiment, a method is provided for improving the respiratory function of a subject requiring improvement of respiratory function, comprising administering to the subject a therapeutically effective amount of the compound of formula (Ia) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby improving the subject's respiratory function.

[0023] Further information is provided regarding compounds of formula (I) or their salts, solvates, prodrugs, or polymorphs for use in improving the respiratory function of a subject.

[0024] Further information is provided regarding compounds of formula (Ia) or their salts, solvates, prodrugs, or polymorphs for use in improving the respiratory function of a subject.

[0025] Improvements in respiratory function can be selected from a reduction in the level of lung contraction, a decrease in the elastic stiffness of the respiratory system, and / or an increase in the ease with which the respiratory system can expand. Preferably, the improvement is selected from a reduction in the level of lung contraction and a decrease in the elastic stiffness of the respiratory system. In yet another embodiment, a composition is provided comprising a compound according to formula (I) or a salt, solvate, prodrug, or polymorph thereof, and a pharmaceutically acceptable excipient.

[0026] In yet another embodiment, a composition is provided comprising a compound according to formula (Ia) or a salt, solvate, prodrug, or polymorph thereof, and a pharmaceutically acceptable excipient.

[0027] The composition may be formulated for oral administration or administration by inhalation or injection.

[0028] The use of the compounds or compositions of the present invention in the preparation of pharmaceuticals for the treatment or prevention of target respiratory diseases is also described.

[0029] In this specification, unless the context requires otherwise, the terms “comprise,” “comprising,” “comprises,” and “comprised,” and their variations thereof, shall not exclude further additives, components, integers, or processes.

[0030] References to prior art in the specification do not constitute a recognition or suggestion that such prior art forms part of the common general knowledge within any jurisdiction, or that such prior art is expected to be reasonably understood by a person skilled in the art, is considered relevant, and / or can be combined with other parts of the prior art.

[0031] Further aspects and embodiments of the present invention described in the preceding paragraphs will become apparent from the following description, given by reference to the accompanying drawings, for example. [Brief explanation of the drawing]

[0032] [Figure 1] In an assay in BEAS-B cells measuring the induction of SCNN1A, which encodes the protein epithelial sodium channel alpha subunit and is a glucocorticoid-regulated gene, the effect of SS9-010 was contrasted with that of PF670462. [Figure 2] In the same experiment as shown in Figure 1, the expression of fibrogen plasminogen activator inhibitor-1 (PAI-1) was measured. [Figure 3] Exposure of BEAS-2B cells to TNF-α with (or without) 30 minutes of pretreatment with either SS9-010 or PF670462 (1-10 μM). [Figure 4] In A549 cells, pretreatment with either PF670462 or SS9-010 (0.1–10 μM) inhibited PAI-1 and CTGF mRAN levels in a concentration-dependent manner and restored the suppression of TGFβ (100 pM) induction in E-cadherin mRNA levels. [Figure 5] The effect of the antifibrotic agent nintedanib is shown for comparison with the degree and efficacy of PF670462. [Figure 6] The CK1 inhibitors PF670462 and SS9-010 (1–10 μM) have been shown to increase the TNF-α (10 ng / ml) induction of IL-8 mRNA expression in culture supernatant and to affect the level of immunoreactivity of IL-8. [Figure 7] Figure 6 shows the expression of CSF-2 (GM-CSF) and its immunoreactivity level in the supernatant of the same experiment. [Figure 8-1] We define several known compounds related to the method of the present invention. [Figure 8-2] We define several known compounds related to the method of the present invention. [Figure 8-3] We define several known compounds related to the method of the present invention. [Figure 8-4] We define several known compounds related to the method of the present invention. [Figure 8-5] We define several known compounds related to the method of the present invention. [Figure 8-6] We define several known compounds related to the method of the present invention. [Figure 8-7] We define several known compounds related to the method of the present invention. [Figure 8-8] We define several known compounds related to the method of the present invention. [Figure 8-9] We define several known compounds related to the method of the present invention. [Figure 8-10] We define several known compounds related to the method of the present invention. [Figure 8-11] We define several known compounds related to the method of the present invention. [Figure 8-12] We define several known compounds related to the method of the present invention. [Figure 8-13] We define several known compounds related to the method of the present invention. [Figure 8-14] We define several known compounds related to the method of the present invention. [Figure 8-15] We define several known compounds related to the method of the present invention. [Figure 8-16] We define several known compounds related to the method of the present invention. [Figure 8-17] We define several known compounds related to the method of the present invention. [Figure 8-18] We define several known compounds related to the method of the present invention. [Figure 8-19] We define several known compounds related to the method of the present invention. [Figure 8-20] We define several known compounds related to the method of the present invention. [Figure 8-21] We define several known compounds related to the method of the present invention. [Figure 8-22] We define several known compounds related to the method of the present invention. [Figure 8-23] We define several known compounds related to the method of the present invention. [Figure 8-24] We define several known compounds related to the method of the present invention. [Figure 8-25] We define several known compounds related to the method of the present invention. [Figure 8-26] We define several known compounds related to the method of the present invention. [Figure 8-27] We define several known compounds related to the method of the present invention. [Figure 8-28] We define several known compounds related to the method of the present invention. [Figure 8-29] We define several known compounds related to the method of the present invention. [Figure 8-30] We define several known compounds related to the method of the present invention. [Figure 8-31] We define several known compounds related to the method of the present invention. [Figure 8-32] We define several known compounds related to the method of the present invention. [Figure 9] Effects of inhaled SS9-010 on bleomycin-induced BAL protein leakage, BAL cell recruitment, and pulmonary fibrosis gene expression in mouse lungs. Female C57Bl / 6 mice were administered bleomycin or saline intranasally on day 0. SS9-010 was administered daily from day 1 to day 3 by inhalation of a 1 mg / mL aerosol for 15 minutes. Bronchoalveolar lavage (BAL) protein and BAL cell counts were evaluated. Pulmonary fibrosis gene expression was also evaluated on day 3. Data are expressed as mean ± SEM (n=6). [Figure 10] Effects of intraperitoneal injection of SS9-010 on bleomycin-induced BAL protein leakage, BAL cell recruitment, and pulmonary fibrosis gene expression in mouse lungs. Female C57Bl / 6 mice were intraperitoneally administered bleomycin or saline on day 0. SS9-010 (3 or 10 mg / kg / day, ip) was administered from day 1 to day 3. Bronchoalveolar lavage (BAL) protein and BAL cell count were evaluated. Pulmonary fibrosis gene expression was also evaluated on day 3. Data are expressed as mean ± SEM (n=4 saline, n=5 other groups). [Figure 11] The effects of oral (forced administration) PF670462 or SS87-058 were investigated in female C57BL6 mice, focusing on liver gene expression. Four-day administration of either PF670462 or SS8-058 at a dose of 30 mg / kg / po resulted in a significant reduction in baseline levels of mRNA encoding fibrosis gene products, PAI-1, and TMP1, three days after intranasal administration of bleomycin on day 0. Data are expressed as mean ± SEM (n=4). [Figure 12] Airway hyperresponse (AHR) in response to inhaled metacholine (MCh) was measured in sham- or ovalbumin (OVA)-sensitized BALB / c mice that received inhalation of SS9-010 (estimated deposition dose of 1 μg) or physiological saline. Resistance (Rn), elastance (E), and compliance (C) were recorded to assess physical changes in the lungs. Data are expressed as mean ± SEM (n=6). [Modes for carrying out the invention]

[0033] It will be understood that the present invention disclosed and defined herein extends to all alternative combinations of two or more individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative embodiments of the present invention.

[0034] Herein, specific embodiments of the present invention will be described in detail. While the present invention will be described in conjunction with its embodiments, it will be understood that the intent is not to limit the invention to those embodiments. Rather, the present invention is intended to cover all alternative forms, variations, and equivalents, which may fall within the scope of the invention as defined by the claims.

[0035] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, and these may be used in carrying out the present invention. The present invention is by no means limited to the methods and materials described herein. It will be understood that the present invention disclosed and defined herein extends to all alternative combinations of two or more individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative embodiments of the present invention.

[0036] All patents and publications referenced herein are incorporated as a whole by reference.

[0037] For the purposes of interpreting this specification, terms used in the singular form also include plural forms, and vice versa.

[0038] The present invention relates to formula (I):

[0039] [C3]

[0040] (In the formula: R1 and R2 are (i) H, C 1〜6 Alkyl, C 2〜6 Alkinyl, C1 alkylC6 aryl, C6 aryl, C 3〜6 Cycloalkyl, and C 3〜5 They are independently selected from the group consisting of heterocyclines; or (ii) R1 and R2, together with the nitrogen atom to which they are bonded, form a heterocyclyl or heteroaryl group; R3 consists of F, Cl, Br, I, CH3, OCH3, OCF2H, OCF3, CO2H, and CO2C 1〜10 Selected from the group consisting of alkyl groups; R4 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 1〜12 Alkyl, C 1〜10 Alkyl C6 aryl, C 1〜6 Alkyl OC 1〜6 Alkyl C6 aryl, C 0〜6 Alkyl heteroaryls, and C 0〜6Selected from the group consisting of alkyl heterocyclyls; The present invention provides compounds (wherein R1, R2, R3, and R4 are each optionally substituted) or salts, solvates, prodrugs, or polymorphs thereof.

[0041] In one embodiment, the present invention provides a compound of formula (I), provided that the compound is not selected from the list of compounds in Figure 8.

[0042] In one embodiment, the present invention provides a compound of formula (I) in which R1 is not H.

[0043] In one embodiment, the present invention is such that R1 is C 1〜3 The present invention provides a compound of formula (I) which is alkyl. In one embodiment, R1 is C 1〜3 If it is an alkyl group, then R2 is H.

[0044] Preferably, R1 is a C substituted with hydroxyl. 1〜3 It is alkyl.

[0045] In one embodiment, the present invention is such that R1 is C 1〜3 The present invention provides a compound of formula (I) which is alkyl and has R2 as H.

[0046] In one embodiment, the present invention is such that R1 is C 2〜6 The present invention provides a compound of formula (I) which is an alkynyl. R1 may be selected from C2 alkynyl, C3 alkynyl, and C4 alkynyl compounds. In one embodiment, R1 is C 2〜6 If it is an alkynyl, then R2 is H.

[0047] In one embodiment, the present invention provides a compound of formula (I) in which R1 is a C6 aryl compound. In one embodiment, when R1 is a C6 aryl compound, R2 is H.

[0048] In one embodiment, the present invention is such that R1 is C 3〜6The present invention provides a compound of formula (I) which is a cycloalkyl compound. R1 may be selected from cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R1 is C 3〜6 If it is a cycloalkyl group, R2 is H.

[0049] In one embodiment, the present invention is such that R1 is C 3〜5 The present invention provides a compound of formula (I) which is a heterocyclyl. R1 may be selected from an oxygen-containing heterocyclyl group, a nitrogen-containing heterocyclyl group, or a sulfur-containing heterocyclyl group, or a heterocyclyl group containing a combination of two or more oxygen, nitrogen, and sulfur atoms. Examples include oxyranyl, thyranyl 1,3-diazetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, terahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothipheneyl, and 1,2- and 1,3-oxathiolanyl. In one embodiment, R1 is C 3〜5 If it is a heterocycline, R2 is H.

[0050] In one embodiment, the present invention provides a compound of formula (I) in which R1 and R2 are both the same. For example, R1 and R2 may both be H, or R1 and R2 may both be C 1〜6 It may be an alkyl group (e.g., methyl, ethyl, propyl, or butyl).

[0051] In one embodiment, the present invention provides a compound of formula (I) in which R1 and R2, together with the nitrogen to which they are bonded, form a heterocyclyl group.

[0052] Preferably, R1 and R2, together with the nitrogen to which they are bonded, form a morpholino group.

[0053] In another preferred embodiment, R1 and R2, together with the nitrogen to which they are bonded, form an N-heterocyclyl group containing 4 to 8 carbon atoms.

[0054] In one embodiment, R3 is selected from halo and CH3.

[0055] In one embodiment, R3 is CH3.

[0056] In one embodiment, R3 is F, Cl, Br, or I.

[0057] Preferably, R3 is F.

[0058] In one embodiment, R4 is C 0〜3 Alkyl C 3〜12 It is a cycloalkyl group.

[0059] In one embodiment, R4 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 3〜12 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 0〜3 Alkyl C 3〜12 It is a cycloalkyl group.

[0060] In a preferred embodiment, R4 is C 3〜12 It is a cycloalkyl group. More preferably, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0061] In one embodiment, R4 is C 1〜2 Alkyl C 3〜12 It is a cycloalkyl group. R4 is C1 alkylC 3〜12 It may be a cycloalkyl. 3〜12 The cycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0062] In a preferred embodiment, R4 is C 0〜3 Alkyl C 3〜12 If it is a cycloalkyl, C 3〜12The cycloalkyl group is the crosslinking portion. More preferably, R4 is selected from the group consisting of adamantyl, norbornyl, and spirocycloalkyl groups.

[0063] In one embodiment, R4 is C 1〜12 It is an alkyl group. R4 can be a methyl, ethyl, propyl, or butyl group.

[0064] In one embodiment, R4 is C 0〜10 It is an alkyl C6 aryl.

[0065] In one embodiment, R4 is C 1〜6 Alkyl OC 1〜6 It is an alkyl C6 aryl.

[0066] In one embodiment, R4 is C 0〜6 It is an alkyl heteroaryl.

[0067] In one embodiment, R4 is C 0〜6 It is an alkyl heterocycline. R4 may be a spiroheteroalkyl moiety.

[0068] Preferably, R4 is 3-azetidinyl, 3-pyrrolodinyl, or 4-piperidyl.

[0069] Preferably, R4 is C 0〜6 In the case of an alkyl heterocyclyl that also contains a nitrogen atom, the nitrogen of the heterocyclyl is substituted by the group R5, where R5 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 1〜12 Alkyl, C 0〜10 Alkyl C6 aryl, C 1〜6 Alkyl OC 1〜6 Alkyl C6 aryl, C 0〜6 Alkyl heteroaryls, and C 0〜6 Selected from the group consisting of alkyl heterocyclines.

[0070] In one embodiment, R5 is C1〜12 alkyl and C 0〜10 selected from alkyl C6 aryl. In one embodiment, C 0〜10 alkyl C6 aryl group is C 1〜6 alkyl C6 aryl.

[0071] Preferably, R5 is C 0〜3 alkyl C 3〜12 cycloalkyl.

[0072] More preferably, R5 is C 3〜12 cycloalkyl or C 0〜6 alkyl heterocyclyl.

[0073] In another preferred form, R5 is a bridging moiety. More preferably, R5 is selected from the group consisting of adamantyl, norbornyl, and spirocycloalkyl or spiroheteroalkyl moieties.

[0074] In one embodiment, R1, R2, R3, and R4 are optionally substituted by one or more groups selected from OH, C 1〜6 alkoxy, halo, amino, mercapto, and C 1〜6 alkyl.

[0075] The present invention relates to formula (Ia):

[0076]

Chemical Formula 4

[0077] (wherein: R1 and R2 are (i) each independently selected from the group consisting of H, C 1〜6 alkyl, C 2〜6 alkynyl, C6 aryl, and C 3〜5 heterocyclyl; or (ii) R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclyl group; R3 is selected from the group consisting of F, Cl, Br, I, and CH3; R4 is C 0〜3 alkyl C 3〜12Cycloalkyl, C 1〜12 alkyl, and C 0〜6 alkylheterocyclyl selected from the group consisting of; wherein each of R1, R2, R3, and R4 is optionally substituted) or a salt, solvate, prodrug, or polymorph thereof.

[0078] In one embodiment, the present invention provides a compound of formula (Ia) on the condition that the compound is not selected from the list of compounds in FIG. 8.

[0079] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is not H.

[0080] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is C 1〜3 alkyl. R1 can be C 1〜3 alkyl substituted by hydroxyl.

[0081] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is C 1〜3 alkyl and R2 is H.

[0082] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is C 2〜6 alkynyl. R1 can be selected from C2 alkynyl, C3 alkynyl, and C4 alkynyl. In one embodiment, when R1 is C 2〜6 alkynyl, R2 is H.

[0083] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is C6 aryl. In one embodiment, when R1 is C6 aryl, R2 is H.

[0084] In one embodiment, the present invention provides a compound of formula (Ia) wherein R1 is C 3〜6The present invention provides a compound of formula (Ia) which is a cycloalkyl compound. R1 may be selected from cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R1 is C 3〜6 If it is a cycloalkyl group, R2 is H.

[0085] In one embodiment, the present invention is such that R1 is C 3〜5 The present invention provides a compound of formula (Ia) that is a heterocyclyl. R1 may be selected from an oxygen-containing heterocyclyl group, a nitrogen-containing heterocyclyl group, or a sulfur-containing heterocyclyl group, or a heterocyclyl group containing a combination of two or more oxygen, nitrogen, and sulfur atoms. Examples include oxyranil, thyranil 1,3-diazetidinil, oxetanil, thietanil, pyrrolidinil, pyrazolidinil, imidazolidinil, terahydrofuranil, 1,3-dioxolanil, tetrahydropyranil, tetrahydrotiphenail, and 1,2- and 1,3-oxathiolanil. In one embodiment, R1 is C 3〜5 If it is a heterocycline, R2 is H.

[0086] In one embodiment, the present invention provides a compound of formula (Ia) in which R1 and R2 are both the same. For example, R1 and R2 may both be H, or R1 and R2 may both be C 1〜6 It may be an alkyl group (e.g., methyl, ethyl, propyl, or butyl).

[0087] Preferably, R1 and R2, together with the nitrogen to which they are bonded, form a morpholino group.

[0088] In another preferred embodiment, R1 and R2, together with the nitrogen to which they are bonded, form an N-heterocyclyl group containing 4 to 8 carbon atoms.

[0089] In one embodiment, the present invention provides a compound of formula (Ia) in which R3 is CH3. In another embodiment, R3 is F, Cl, Br, or I. Preferably, R3 is F or Cl.

[0090] In one embodiment, the present invention provides a compound of formula (Ia) wherein R4 is C 0〜3 alkyl C 3〜12 cycloalkyl.

[0091] In one embodiment, R4 is C 0〜3 alkyl C 3〜12 cycloalkyl, wherein the C 3〜12 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and R4 is C 0〜3 alkyl C 3〜12 cycloalkyl.

[0092] In a preferred form, R4 is C 3〜12 cycloalkyl. More preferably, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0093] In one embodiment, R4 is C 1〜2 alkyl C 3〜12 cycloalkyl. R4 can be C1 alkyl C 3〜12 cycloalkyl. The C 3〜12 cycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0094] In a preferred form, when R4 is C 0〜3 alkyl C 3〜12 cycloalkyl, the C 3〜12 cycloalkyl group is a bridging moiety. More preferably, R4 is selected from the group consisting of adamantyl, norbornyl, and spirocycloalkyl moieties.

[0095] In one embodiment, the present invention provides a compound of formula (Ia) wherein R4 is C 1〜12 alkyl. R4 can be a methyl, ethyl, propyl, or butyl group.

[0096] In one embodiment, the present invention provides a compound of formula (Ia) wherein R4 is C0〜6 The present invention provides a compound of formula (Ia) which is an alkyl heterocyclyl. Preferably, R4 is 3-azetidinyl, 3-pyrrolodinyl, or 4-piperidyl. R4 may be a spiroheteroalkyl moiety.

[0097] In one embodiment, R4 is C 0〜6 It is an alkyl heterocycline containing a nitrogen atom. The nitrogen may be substituted with the group R5, where R5 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 1〜12 Alkyl, C 0〜10 Alkyl C6 aryl, C 1〜6 Alkyl OC 1〜6 Alkyl C6 aryl, C 0〜6 Alkyl heteroaryls, and C 0〜6 Selected from the group consisting of alkyl heterocyclines.

[0098] In one embodiment, R5 is C 1〜12 Alkyl and C 0〜10 Selected from alkylC6aryl. In one embodiment, C 0〜10 The alkylC6 aryl group is C 1〜6 It is an alkyl C6 aryl.

[0099] In one embodiment, R1, R2, R3, and R4 are OH, C 1〜6 Alkoxy, halo, amino, mercapto, and C 1〜6 It is optionally substituted with one or more groups selected from alkyl groups.

[0100] In this specification, the term “alkyl” refers to a linear or branched hydrocarbon group having 1 to 12 or any range between those carbon atoms; that is, it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Alkyl groups are optionally substituted with substituents, and multiple degrees of substitution are permitted. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, and isopentyl.

[0101] In this specification, the term "C 1〜3 Alkyl," "C 1〜4 "Alkyl" and "C 1〜6 "Alkyl" and similar terms refer to the previously defined alkyl groups, each containing at least one and at most three, four, or six carbon atoms, or any range in between (for example, alkyl groups containing 2 to 5 carbon atoms, i.e., 2, 3, 4, or 5 carbon atoms, are also C 1〜6 (Within the range of C) 0〜2 When terms like "alkyl" are used, there may be no alkyl group at all, or there may be an alkyl group containing one or two carbon atoms.

[0102] The term "alkynyl" refers to a partially unsaturated, straight or branched hydrocarbon group containing 2 to 6 carbon atoms, i.e., 2, 3, 4, 5, or 6 carbon atoms. Specific examples of alkynyl groups include ethynyl, propynyl, butynyl, acetylenyl, and propargyl groups. Preferably, the alkynyl group has one or two triple bonds. The triple bonds may be terminal or internal.

[0103] In this specification, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and the term "halo" refers to a halogen group, fluoro(-F), chloro(-Cl), bromo(-Br), and iodine(-I). Preferably, "halo" is fluoro or chloro.

[0104] In this specification, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring. Similarly, the term "C 3〜7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having 3 to 7 carbon atoms or any range between them. For example, C 3〜7 Cycloalkyl groups may also include cycloalkyl groups containing 4 to 6 (i.e., 4, 5, or 6) carbon atoms. The alkyl group is as previously defined and may be substituted. Examples of "C" useful in this invention are... 3〜7 The "cycloalkyl" group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0105] The cycloalkyl group may optionally be fused to one or more heterocyclic or cycloalkyl rings. The cycloalkyl ring may be substituted at any carbon atom on the ring by another cycloalkyl or heterocyclic moiety to form a spirocycloalkyl or spiroheteroalkyl compound.

[0106] Two non-adjacent atoms on a cycloalkyl group may be crosslinked by an alkyl or heteroalkyl group to form a crosslinked system. Preferably, the crosslinking group has a length of 1 to 3 atoms.

[0107] In this specification, the term “heterocyclic” or “heterocyclyl” refers to a non-aromatic heterocyclic ring that is saturated, has one or more degrees of unsaturation, and contains one or more heteroatom substitutions selected from S, S(O), S(O)2, O, or N. 3〜7 A "heterocyclyl" refers to a non-aromatic cyclic hydrocarbon ring having 3 to 7 carbon atoms (i.e., 3, 4, 5, 6, or 7 carbon atoms) and containing one or more heteroatom substitutions as referred herein. The heterocyclic portion may be substituted, and multiple degrees of substitution are permitted. 3〜7 "Heterocycline" is C 4〜5 , C 5〜7 , C 6〜7 , C 4〜7 , C 4〜6 , and C 5〜6This also includes heterocyclyl groups containing carbon atoms. Preferably, the heterocycle contains 4 to 6 carbon atoms and 1 or 2 heteroatoms. More preferably, the heterocycle contains 5 carbon atoms and 1 heteroatom, or 4 carbon atoms and 2 heteroatom substitutions, or 5 carbon atoms and 1 heteroatom. Such rings may optionally be fused to one or more other "heterocyclic" rings or cycloalkyl rings. Examples of "heterocyclic" parts include, but are not limited to, tetrahydrofuran, pyran, oxetane, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, N-methylpiperazinyl, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, and tetrahydrothiophene.

[0108] A heterocyclic group may be substituted at any of the carbon atoms on the ring by another heterocyclic or cycloalkyl moiety to form a spirocycloalkyl or spiroheteroalkyl compound.

[0109] Two non-adjacent atoms on a heterocyclic group may be further crosslinked by an alkyl or heteroalkyl group to form a crosslinking system. Preferably, the crosslinking group has a length of 1 to 3 atoms.

[0110] As an example of a substituted heterocyclic group, the term "C 0〜2 Alkyl C 3〜7 A "heterocyclyl" is a heterocyclyl group that either contains no alkyl group at all as a linker between the compound and the heterocycle, or contains an alkyl group containing one or two carbon atoms as a linker between the compound and the heterocycle (i.e., a heterocycle, a -CH2-heterocycle, or a -CH2CH2-heterocycle). These heterocycles may be further substituted.

[0111] The substituted cycloalkyl and heterocyclyl groups may be substituted with the preferred substituents listed below.

[0112] In this specification, the term “aryl” refers to an optionally substituted benzene ring or an optionally substituted benzene ring system that condenses with one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or naphthalene ring systems. Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and their substituted derivatives. Preferred aryl groups include arylamino, aralkyl, aralkoxy, and heteroaryl groups.

[0113] In this specification, the term "heteroaryl" refers to a monocyclic five-, six-, or seven-membered aromatic ring, or a fused bicyclic or tricyclic aromatic ring system containing at least one monocyclic five-, six-, or seven-membered aromatic ring. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen heteroatoms, where N-oxides, sulfur oxides, and dioxides are acceptable heteroatomic substitutions, and may be optionally substituted by up to three members. Examples of the "heteroaryl" group used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxopyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, and their substituted variants.

[0114] As used herein, “substituent” refers to a molecular portion that is covalently bonded to an atom within the molecule in question. For example, a “ring substituent” may be a portion such as a halogen, alkyl group, or other substituent as described herein that is covalently bonded to a ring member atom, preferably a carbon or nitrogen atom. As used herein, “substituted” means that one or more hydrogen atoms on a specified atom are replaced by a substituent selected from those shown, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity.

[0115] Throughout this specification, terms such as "optionally substituted" or "may be substituted" indicate that a group may or may not be further substituted with one or more non-hydrogen substituents, or may be condensed (forming a polycyclic system). Suitable chemically viable substituents for specific functional groups will be apparent to those skilled in the art.

[0116] Examples of substituents include, but are not limited to, the following: C 1〜6 Alkyl, C 1〜6 Haloalkyl, C 1〜6 Haloalkoxy, C 1〜6 Hydroxyalkyl, C 3〜7 Heterocyclyl, C 3〜7 Cycloalkyl, C 1〜6 Alkoxy, C 1〜6 Alkyl sulfanyl, C 1〜6 Alkylsulfenyl, C 1〜6 Alkyl sulfonyl, C 1〜6 Alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaloyl, acyloxy, aroyloxy, heteroaloyloxy, alkoxycarbonyl, nitro, cyano, halogen, ureido, or C 1〜6Perfluoroalkyl. In one embodiment, a cyclic or heterocyclic substituent may form a spirocycloalkyl or spiroheteroalkyl substituent together with the carbon in the substituted portion of the cyclic or heterocyclic group. In another embodiment, the cyclic or heterocyclic substituent may be crosslinked.

[0117] Any of these groups may be further substituted with any of the aforementioned groups, where appropriate. For example, alkylamino, or dialkylamino, C 1〜6 Alkoxy, etc.

[0118] While salts of the compounds of formulas (I) and (Ia) are preferably pharmaceutically acceptable, it will be recognized that pharmaceutically unacceptable salts are also within the scope of this disclosure, as they are useful as intermediates in the preparation of pharmaceutically acceptable salts.

[0119] The term "pharmaceutically acceptable" may be used to refer to any pharmaceutically acceptable salt, hydrate, or prodrug, or any other compound, that can (directly or indirectly) provide the compound of formula (I) or formula (Ia), or its active metabolite or residue, to a subject at the time of administration.

[0120] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0121] Basic salts include, but are not limited to, those formed from pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, and ammonium; alkylammonium salts such as those formed from triethylamine; alkoxyammonium salts such as those formed from ethanolamine; and salts formed from ethylenediamine, choline, or amino acids such as arginine, lysine, or histidine. General information regarding the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is described in common books such as "Handbook of Pharmaceutical Salts" PHStahl, CGWermuth, 1st edition, 2002, Wiley-VCH.

[0122] Basic nitrogen-containing groups can be quaternized by active agents such as lower alkyl halides, e.g., methyl chloride, ethyl chloride, propyl chloride, and butyl chloride; methyl bromide, ethyl bromide, propyl bromide, and butyl bromide, as well as methyl iodide, ethyl iodide, propyl iodide, and butyl iodide; dialkyl sulfates, e.g., dimethyl sulfate and diethyl sulfate; and others.

[0123] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently bonded to a free amino and / or amide group of a compound of formula (I) or (Ia). The amino acid residues include 20 naturally occurring amino acids, usually represented by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which a carbonate, carbamate, amide, or alkyl ester is covalently bonded to the above substituents of formula (I) or (Ia) by a carbonyl carbon prodrug side chain. Prodrugs may include irreversible and reversible inhibitors of covalent bonding.

[0124] In the case of solid compounds, it will be understood by those skilled in the art that the compounds, agents, and salts of the present invention may exist in different crystalline or polymorphic forms, but all are intended to be within the scope of the present invention and the explicitly stated formulas.

[0125] The term "polymorph" includes all crystalline forms of the compound of formula (I) or formula (Ia), including the anhydrous form, the hydrated form, the solvate form, and the mixed solvate form.

[0126] In yet another embodiment, a composition is provided comprising a compound according to formula (I) or a salt, solvate, prodrug, or polymorph thereof, and a pharmaceutically acceptable excipient.

[0127] In yet another embodiment, a composition is provided comprising a compound according to formula (Ia) or a salt, solvate, prodrug, or polymorph thereof, and a pharmaceutically acceptable excipient.

[0128] An appropriate dose level would generally be about 0.01 to 500 mg per kg of patient weight per day, which can be administered as a single dose or in repeated doses. Preferably, the dose level would be about 0.1 to 250 mg / kg per day; more preferably, about 0.5 to 100 mg / kg per day. Preferred dose levels could be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dose could be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is provided in the form of tablets containing preferably 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient, for dose adjustment according to the symptoms of the patient being treated. The compound may be administered 1 to 4 times per day, preferably in a regimen of once or twice per day. However, it will be understood that the specific dose levels and dose frequencies for a particular patient may vary, depending on various factors including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the specific condition, and the host receiving the therapy. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0129] For inhaled products, typical inhalation doses are lower than those for other forms of medication, starting at 1 microgram per single inhalation and increasing to 1000 micrograms. In a preferred form, the dose is in the range of 25 to 250 micrograms per inhalation. In another preferred form, the dose is in the range of 500 to 1000 micrograms per inhalation. In yet another form, the dose is selected from the group consisting of any range including 1, 2.5, 10.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 micrograms per inhalation, or any range including two of these values. The medication may be administered as one inhalation per day, or as two inhalations per day, increasing up to four times.

[0130] The pharmaceutical composition may further contain other therapeutically active compounds that are typically used to treat the disclosed disorders or conditions. The selection of appropriate agents for use in combination therapy can be made by those skilled in the art in accordance with conventional pharmaceutical principles. Combinations of therapeutic agents may act synergistically to provide treatment or prevention of the various disorders or conditions disclosed herein. This method can be used to obtain therapeutic efficacy with lower doses of each agent and reduce the potential for adverse side effects.

[0131] The compounds and compositions of the present invention may be formulated for any suitable route of administration, including, for example, external use (e.g., transdermal or ocular), pulmonary, oral, buccal, intranasal, vaginal, rectal, or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, intraspinal, intracranial, intramedullary, intraocular, periocular, intraorbital, intraarticular, synovial bursa, and intraperitoneal injections, as well as any similar injection or infusion techniques. In certain embodiments, compositions in forms suitable for oral or parenteral use are preferred. Suitable oral forms include, for example, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In further embodiments, the compositions provided herein may be formulated as lyophilized products.

[0132] In a preferred form, the composition is suitable for administration into the airway. In another form, the composition is suitable for oral administration.

[0133] Various dose units are preferably provided as tablets, capsules, lozenges, sugar-coated tablets, gums, or other types of solid formulations of different doses. Capsules may contain powders, liquids, or gels. Solid formulations may be swallowable or be suckable or chewable (either crumbled or rubbery). The present invention envisions dose unit holding devices other than blister packs; for example, packaging such as bottles, tubes, canisters, and packets. The dose units may further contain conventional excipients known in pharmaceutical formulation practice, such as binders, gelling agents, fillers, tableting lubricants, disintegrants, surfactants, and colorants; for suckable or chewable formulations.

[0134] Compositions for oral use may further contain one or more components, such as sweeteners, flavorings, colorings, and / or preservatives, to provide an appealing and palatable formulation. Tablets contain the active ingredient mixed with physiologically acceptable excipients suitable for tablet formulation. Such excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants, such as corn starch or alginic acid; binders, such as starch, gelatin, or gum arabic; and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets may be left uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used.

[0135] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0136] The aqueous suspension contains an active ingredient mixed with an excipient suitable for the manufacture of the aqueous suspension. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, as well as dispersants or wetting agents, such as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, condensation products of ethylene oxides and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavorings, and one or more sweeteners, such as sucrose or saccharin.

[0137] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and / or flavorings, such as those mentioned above, can be added to provide a palatable oral preparation. Such suspensions can be preserved by adding antioxidants such as ascorbic acid.

[0138] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are provided by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweeteners, flavoring agents, and coloring agents may also be present.

[0139] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as gum arabic or gum tragacanth, natural phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydride, such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide, such as polyoxyethylene sorbitan monoleate. The emulsion may also contain one or more sweeteners and / or flavorings.

[0140] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also include one or more lubricants, preservatives, flavorings, and / or colorings.

[0141] The compositions of the present invention can be formulated for topical or external administration, such as for application to the skin. Formulations for external administration typically comprise a topical vehicle combined with the active agent, with or without additional optional components.

[0142] Suitable topical vehicles and additional components are well known in the art, and it will be evident that the selection of the vehicle depends on the specific physical form and delivery method. Topical vehicles include organic solvents, e.g., alcohols (e.g., ethanol, isopropyl alcohol, or glycerin), glycols, e.g., butylene, isoprene, or propylene glycol, aliphatic alcohols, e.g., lanolin, mixtures of water and organic solvents, and mixtures of alcohols and organic solvents such as glycerin, lipid-based substances, e.g., fatty acids, oils such as mineral oils, and acylglycerols including natural or synthetic fats, glycerophospholipids, sphingolipids, and waxes, protein-based substances, e.g., collagen and gelatin, silicone-based substances (both non-volatile and volatile), and hydrocarbon-based substances, e.g., microsponges and polymer matrices.

[0143] The composition may further include one or more components adapted to improve the stability or efficacy of the formulation to be applied, such as stabilizers, suspending agents, emulsifiers, viscosity modifiers, gelling agents, preservatives, antioxidants, skin penetration enhancers, humectants, and sustained-release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may include microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles, or nanocapsules.

[0144] Topical formulations can be prepared in various physical forms, including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays, and skin patches. The physical appearance and viscosity of such forms can be controlled by the presence and amount of emulsifiers and viscosity modifiers present in the formulation. Solids are generally rigid, non-flowing, and are usually formulated as bars or sticks, or in the form of particulate matter. Solids can be opaque or transparent and may optionally contain solvents, emulsifiers, humectants, emollients, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to each other, differing mainly in their viscosity. Both lotions and creams can be opaque, translucent, or transparent and often contain emulsifiers, solvents, and viscosity modifiers, as well as humectants, emollients, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared in a variety of viscosities, from thick or high viscosity to dilute or low viscosity. These formulations, like lotions and creams, may contain solvents, emulsifiers, humectants, emollients, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product. Liquid formulations are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, humectants, emollients, emollients, fragrances, dyes / colorants, preservatives, and other active ingredients that increase or enhance the efficacy of the final product.

[0145] Emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, and nonionic emulsifiers such as polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate, and glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic rubbers such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. Gel compositions can be formed by adding gelling agents such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaternium, hydroxyethyl ceilulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carbomer, or ammonia-modified glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic, and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used in topical formulations.

[0146] Preservatives include, but are not limited to, antimicrobial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate / ascorbic acid, and propyl gallate. Suitable humectants include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable fragrances and colorants include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that can be included in topical formulations include, but are not limited to, abrasives, absorbents, anti-caking agents, defoamers, antistatic agents, astringents (such as witch hazel extract), alcohols and herbal extracts such as chamomile extract, binders / excipients, buffers, chelating agents, film-forming agents, conditioning agents, propellants, opacifiers, pH adjusters, and protective agents.

[0147] Typical modes of delivery for topical compositions include finger application, application using physical applicators such as cloth, tissue paper, cotton swabs, sticks, or brushes, spraying or foaming including mist, aerosols, drip application, spraying, immersion, and rinsing. Controlled-release vehicles may also be used, and compositions may be formulated for transdermal administration (e.g., as transdermal patches).

[0148] Pharmaceutical compositions may be formulated as sustained-release formulations, such as capsules, that provide a slow release of the modifier after administration. Such formulations are generally prepared using well-known techniques and may be administered, for example, orally, rectally, or subcutaneously, or by implantation at a desired target site. Carriers for use in such formulations may be biocompatible and biodegradable. Preferably, the formulation provides a relatively constant level of modifier release. The amount of modifier contained in the sustained-release formulation depends, for example, on the site of implantation, the rate and expected duration of release, and the nature of the disorder to be treated or prevented.

[0149] Pharmaceutical compositions may be formulated as inhalation formulations, including sprays, mists, or aerosols, for example, for administration to the airways. This may be particularly preferred for the treatment of respiratory diseases, including airway or pulmonary conditions, including fibrosis as described herein. Inhalation formulations may be for application to the upper respiratory tract (including the nasal cavity, pharynx, and larynx) and the lower respiratory tract (including the trachea, bronchi, and lungs). In inhalation formulations, the compositions or combinations provided herein may be delivered by any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered-dose inhalers using propellants such as HFA or physiologically and environmentally acceptable propellants. Other suitable devices include breath-operated inhalers, high-dose dry powder inhalers, and aerosol nebulizers. Aerosol formulations for use in the methods of the subject may typically be filled into conventional aerosol containers containing a propellant, surfactant, and cosolvent, and closed by a suitable metered-dose valve. Depending on whether the application is to the upper respiratory tract (including the nasal cavity, pharynx, and larynx) or the lower respiratory tract (including the trachea, bronchi, and lungs), different devices and excipients may be used and can be determined by those skilled in the art. Furthermore, processes for atomizing and forming nanoparticles of formulations of the compounds described herein for use in inhalers such as dry powder inhalers are also known to those skilled in the art.

[0150] The inhalation composition may include a liquid or powdered composition containing an active ingredient suitable for atomization and intrabronchial use, or an aerosol composition administered by an aerosol unit that dispenses a measured dose. A preferred liquid composition contains the active ingredient in an aqueous, pharmaceutically acceptable inhalation solvent, such as isotonic saline or bacteriostatic water. The liquid is administered by a pump or squeeze-actuated spray dispenser, or by inhaling the required dose of the liquid composition into the patient's lungs, or by any other conventional means that enables this. A preferred formulation with a liquid carrier, for example, as a nasal spray or nasal preparation, contains an aqueous or oily solution of the active ingredient. Examples of inhalation drug delivery devices are described in Ibrahim et al. Medical Devices: Evidence and Research 2015:8 131-139, intended for use in the present invention.

[0151] In another embodiment, a method is provided for treating or preventing a respiratory disease in a subject requiring treatment or prevention of the respiratory disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby treating or preventing the respiratory disease of the subject.

[0152] Further provided are compounds of formula (I) or salts, solvates, prodrugs, or polymorphs thereof for use in the treatment or prevention of respiratory diseases in subjects requiring treatment or prevention of respiratory diseases.

[0153] The use of the compound of formula (I) or its salts, solvates, prodrugs, or polymorphs in the preparation of pharmaceuticals for the treatment or prevention of respiratory diseases in subjects requiring treatment or prevention of respiratory diseases is also described.

[0154] In another embodiment, a method is provided for treating or preventing a respiratory disease in a subject requiring treatment or prevention of the respiratory disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia) or its salt, solvate, enantiomer, prodrug, or polymorph, thereby treating or preventing the respiratory disease of the subject.

[0155] Further provided are compounds of formula (Ia) or salts, solvates, prodrugs, or polymorphs thereof for use in the treatment or prevention of respiratory diseases in subjects requiring treatment or prevention of respiratory diseases.

[0156] The use of the compound of formula (Ia) or its salts, solvates, prodrugs, or polymorphs in the preparation of pharmaceuticals for the treatment or prevention of respiratory diseases in subjects requiring treatment or prevention of respiratory diseases is also described.

[0157] In this specification, “preventing” or “prevention” means at least reducing the likelihood (or susceptibility) to developing a disease or disability (i.e., preventing at least one clinical symptom of a disease from occurring in a patient who may be exposed to or predisposed to the disease but has not yet experienced or shown any symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are well known to physicians.

[0158] The terms “treatment” or “treating” of a subject include the application or administration of the compounds of the present invention to a subject (or the application or administration of the compounds of the present invention to cells or tissues derived from the subject) for the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, reducing, modifying, treating, lessening, worsening, relieving, improving, or influencing a disease or condition, the symptoms of a disease or condition, or the risk (or susceptibility to such risk) of a disease or condition. The term “treating” means any manifestation of successful treatment or improvement of a wound, condition, or pathology, including any objective or subjective parameter such as relief; remission; a decrease in the rate of worsening; a decrease in the severity of the disease; stabilization, reduction of symptoms or making the wound, condition, or pathology more tolerable to the subject; a slowing of the rate of degeneration or decline; making the final stage of degeneration less debilitating; or improvement of the physical or mental health of the subject.

[0159] In this specification, the term "antagonizing" means "decreasing" or "reducing." A sufficient period may be one week, one week and one month, one to two months, or two months or more. In chronic conditions, the compounds of the present invention may, if convenient, be administered for life.

[0160] The term "respiratory" refers to the process by which oxygen is taken into the body and carbon dioxide is expelled through body tissues including the nose, throat, larynx, trachea, bronchi, and lungs.

[0161] The term “respiratory disease” or “respiratory condition” refers to any one of several diseases that may involve inflammation and / or tissue remodeling affecting the components of the respiratory system, including the upper respiratory tract (including the nasal cavity, pharynx, and larynx) and the lower respiratory tract (including the trachea, bronchi, and lungs). Such conditions include pulmonary fibrosis (interstitial lung disease), sinusitis, influenza, sarcoidosis, bronchial cancer (including, but not limited to, non-small cell and small cell lung cancer, and lung metastases from tumors of other organs), silicosis, pneumoconiosis, acute lung injury, ventilation-induced lung injury, congenital emphysema, bronchopulmonary dysplasia, bronchiectasis, atelectasis, nasal polyps, asbestosis, mesothelioma, pulmonary eosinophilia, diffuse pulmonary hemorrhage syndromes, bronchiolitis obliterans, alveolar proteinosis, collagen and vascular disorders affecting the lungs, and cough. Preferably, respiratory diseases are obstructive airway diseases, and such diseases include asthmatic conditions such as hay fever, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, stress-induced asthma and virus-induced asthma, obesity-related asthma, occupational asthma, thunderstorm asthma, asthma-COPD overlap syndrome (ACOS), chronic obstructive pulmonary diseases such as chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous diseases, as well as other lung diseases including inflammation such as cystic fibrosis, pigeon disease, farmer's lung disease, acute respiratory distress syndrome, pneumonia of fungal, viral, bacterial, mixed, or unknown etiologies, aspiration or inhalation wounds, pulmonary fat embolism, and pulmonary acidosis (inflammation). These include inflammation, acute pulmonary edema, acute altitude sickness, post-cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension in neonates, perinatal aspiration syndrome, hyalineosis, acute pulmonary thromboembolism, heparin-protamine reaction, sepsis, status asthmaticus, and hypoxia. Inflammation of the upper and lower respiratory tracts may be associated with or caused by viral infections or allergens.It is predicted that the anti-inflammatory activity of compounds administered alone or in combination with glucocorticoids will be particularly suitable for the treatment of these diseases or conditions.

[0162] Respiratory diseases or conditions may be associated with or caused by allergens such as house dust mites. Respiratory diseases or conditions may be the result of allergen-induced inflammation. The present invention is particularly applicable to the exacerbation of allergic diseases of the airways or lungs and exacerbations resulting from viral infections (e.g., RSV infection).

[0163] Symptoms of respiratory illness may include cough, excessive sputum production, shortness of breath, or chest tightness accompanied by audible wheezing. Exercise capacity may be severely limited. In asthma, FEV1.0 (forced expiratory volume in one second), as a percentage of what is predicted from the chart based on weight, height, and age, may decrease, as may maximal expiratory flow in forced exhalation. In COPD, FEV1.0 as a ratio of forced vital capacity (FVC) typically decreases to less than 0.7. In IPF, there is a progressive decline in FVC. The impact of each of these conditions can also be measured by days of lost work / school, sleep disturbances, need for bronchodilators, and need for glucocorticoids, including oral glucocorticoids. Further measures of the impact of these conditions include demonstrated health-related quality of life measures. Medical imaging procedures, including but not limited to X-ray, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, optical coherence tomography, and fluoroscopy, can also be used to evaluate diseases and therapeutic responses.

[0164] The presence, improvement, treatment, or prevention of respiratory disease may be determined by any clinically or biochemically relevant means of the subject or biopsy material obtained therefrom. For example, parameters measured may include the presence or degree of lung function; signs and symptoms of obstruction; exercise tolerance; nocturnal awakenings; days when one is unable to attend school or work; use of bronchodilators; ICS dosage; use of oral gastrointestinal glands; need for other drug therapies; need for medical treatment; and hospitalization.

[0165] In this specification, the term “asthma” refers to a respiratory disorder characterized by transient shortness of breath caused by one or a combination of three main causes, including 1) bronchospasm (i.e., variable and reversible airway obstruction due to muscular contractions of the airways), 2) inflammation of the airway covering, and 3) bronchial hyperreactivity resulting in excessive mucus in the airways, which can be triggered by exposure to an allergen or combination of allergens (i.e., dust mites and mold), a viral or bacterial infection (i.e., the common cold virus), environmental pollutants (i.e., chemical fumes or smoke), physical exercise (i.e., during exercise), stress, or inhalation of cold air. In this specification, the term “asthmatic condition” refers to the characteristic of an individual to suffer an asthmatic attack upon exposure to one or more of the asthmatic triggers for that individual. An individual may be characterized as having, for example, allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, virus-induced asthma, or cold-induced asthma.

[0166] The efficacy of asthma treatment can be measured by methods well known in the art, such as increased lung function (spirometry), reduced asthma exacerbations, increased morning maximum expiratory flow rate, reduced rescue medication use, reduced daytime and nighttime asthma symptoms, increased asthma-free days, increased time to asthma exacerbation, and increased forced expiratory volume in one second (FEV1.0).

[0167] In this specification, the terms “chronic obstructive pulmonary disease” and “COPD” are interchangeable and refer to a chronic disease or combination of diseases characterized by a decrease in maximum expiratory flow rate and a slowing of forced emptying of the lungs that does not significantly change over several months and is not restored, or is only slightly restored, by conventional bronchodilators. Most commonly, COPD is a combination of chronic bronchitis, i.e., the presence of cough and sputum for more than three months over a continuous period of about two years, and emphysema, i.e., alveolar damage. However, COPD may include chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous diseases, and combinations thereof. Chronic obstructive pulmonary disease is a condition resulting from chronic lung injury that is not exclusively, but usually, induced by exposure to tobacco smoke. Other harmful airborne pollutants, such as exhaust from indoor cooking and automobiles, can increase or increase the risk of COPD over long periods, similar to aging.

[0168] The phrase “conditions of the airways or lungs including fibrosis” or “conditions of the airways or lungs having a fibrous component” includes any disease or condition in which there is excessive formation or development of fibrous connective tissue (fibrosis) in the airways or lungs, resulting in scarred (fibrous) tissue. This includes interstitial lung diseases such as pulmonary fibrosis, lung fibrosis, or idiopathic pulmonary fibrosis (IPF). More precisely, pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lungs. Scarred tissue is replaced by healthy tissue and becomes inflamed. This damage to the lung tissue causes stiffness in the lungs, which subsequently makes breathing more difficult. Pulmonary fibrosis can result from radiation damage as well as exposure to therapeutic agents such as bleomycin.

[0169] Idiopathic pulmonary fibrosis (IPF) is a specific manifestation of idiopathic interstitial pneumonia (IIP), a type of interstitial lung disease. Interstitial lung disease, also known as diffuse parenchymal lung disease (DPLD), refers to a group of lung diseases that affect the interstitium. Microscopically, lung tissue obtained from IPF patients shows a distinctive set of histological features known as usual interstitial pneumonia (UIP). Therefore, UIP is a pathological expression of IPF.

[0170] The presence, improvement, treatment, or prevention of airway or lung conditions, including fibrosis, particularly pulmonary fibrosis / lung fibrosis or idiopathic pulmonary fibrosis, may be assessed by any clinically or biochemically relevant means of the subject or biopsy material obtained from the subject. For example, the rate of decrease in FVC or the appearance of high-resolution computed tomography images of the lung may be useful in diagnosing IPF. Furthermore, parameters measured may include the presence or degree of fibrosis, the content of collagen, fibronectin, or other extracellular matrix proteins, the proliferation rate of cells or extracellular matrix components within cells, or the conversion of cells to myofibroblasts.

[0171] In one embodiment, the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, interstitial lung disease (such as idiopathic pulmonary fibrosis), and other conditions related to tissue remodeling, primary or secondary lung tumors, hay fever, chronic and acute sinusitis, and chronic and acute viral, fungal, and bacterial infections of the airways.

[0172] In one embodiment, the improvement in respiratory function may be selected from a reduction in the level of lung contraction, a reduction in the elastic stiffness of the respiratory system, and / or an increase in the ease with which the respiratory system can expand. Preferably, the improvement is selected from a reduction in the level of lung contraction and a reduction in the elastic stiffness of the respiratory system. In yet another embodiment, a composition is provided comprising a compound according to formula (I) or a salt, solvate, prodrug, or polymorph thereof, and a pharmaceutically acceptable excipient.

[0173] The therapeutically effective dose of the formulation depends on the severity of the specific respiratory disease indication (e.g., severe chronic asthma), the patient's medical history and response, and the judgment of the attending physician. The formulation may be administered to the patient as a single dose or over a series of treatments. An initial candidate dose may be administered to the patient, and an appropriate dose and treatment regimen may be established by monitoring the patient's progress using conventional techniques well known to those skilled in the art. Preferably, the therapeutically effective concentration of the active compound would be in the range of 0.1 nM to 100 μM. More preferably, the range would be 0.1 to 10 μM. However, while inhalation delivery may expose cells in the airways to concentrations exceeding those cited above for a short period, it will be recognized that the drug is diluted in the airway surface fluids during that time and is also absorbed from the airway and lung surfaces.

[0174] In one embodiment, the therapeutic method of the present invention further comprises administering a concomitant agent for the target disease indication. For example, concomitant asthma drug therapies (both chronic and acute) that may be used in conjunction with the method of the present invention include, but are not limited to, the following: inhaled and oral steroids (e.g., beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, mometasone); systemic corticosteroids (e.g., methylprednisolone, prednisolone, prednisone, dexamethasone, and deflazacort); inhaled or oral β2-adrenergic receptor agonists (e.g., salmeterol, formoterol, bitolterol) (e.g., pirbuterol, vilanterol, terbutaline, bambuterol, and albuterol); cromoline and nedocromil; antiallergic opthalmic drug therapies (e.g., dexamethasone); agents that modulate the production and action of transforming growth factor-β, including pirfenidone and nintedanib; methylxanthine and other phosphodiesterase inhibitors (e.g., theophylline and mepyramin-theophylline acetate, roflumilast); leukotriene modulators (e.g., zaphne Irulukast, Zilloton, Montekulast, and Pranlukast; anticholinergic agents (e.g., ipatropium bromide); other therapeutic antibodies in any format (e.g., antibodies against interleukin-5 such as mepolizumab, or antibodies against IgE such as omalizumab, monoclonal forms of these antibodies, Fab, scFV, polyvalent compositions, heterologous antibodies, etc.), natural or engineered antibody mimetics (e.g., anticarin) or natural, engineered, or synthetic peptides; thromboxane A2 synthetase inhibitors; thromboxane prostanoid receptor antagonists; other eicosanoid moduloassides (e.g., alprostadil vs. PGE1, dinoprostone vs. PGE2, epoprostenol vs. prostacyclin and PGI2 analogs (e.g., PG12 beraprost), seratrodast, phosphodiesterase 4 isoenzyme inhibitors, thromboxane A2 synthetase inhibitors (e.g., ozmagrel, dazmegrel, or ozagrel);Ditec (low-dose disodium cromoglycate and fenoterol); platelet-activating factor receptor antagonists; antihistamines or histamine antagonists: promethazine, chlorpheniramine, loratadine, cetirazine, azelastine; thromboxane A2 receptor antagonists; bradykinin receptor antagonists (e.g., icatibant); agents that inhibit activated eosinophil and T cell recruitment (e.g., ketotifen), IL-13 blockers (e.g., soluble IL-13 receptor fragments), IL-4 blockers (e.g., soluble IL-4 receptor fragments); ligands that bind to IL-13 or IL-4 and block their activity, and xanthine derivatives (e.g., pentoxifylline); chemokine receptor antagonists and CRTH2 receptor antagonists.

[0175] In certain embodiments, the therapeutic methods of the present invention involve the simultaneous provision of an inhibitory RNA molecule (RNA interference molecule) to a target for the purpose of reducing, inhibiting, or preventing the expression of a gene encoding a target protein. For example, the inhibitory RNA molecule may be used to reduce or inhibit the expression of one or more proteins associated with pathogens (viruses, bacteria, fungi) or mammalian cells, such as, without limitation, casein kinase 1 isoforms and other components of the clock regulatory network (e.g., ARNT1, periods 1-3) and other proteins that contribute to inflammatory responses in the respiratory system, such as interleukin-5 and NALP inflammasome.

[0176] Those skilled in the art will be familiar with the various means of utilizing inhibitory RNA molecules for the purpose of interfering with the expression of a target gene. For example, the inhibitory RNA molecule may be any one of the following: short interfering RNA (siRNA), microRNA mimetic (miRNA), short hairpin RNA (shRNA), or long double-stranded RNA molecule. The inhibitory RNA molecule may be administered directly to the subject requiring treatment (e.g., by inhalation, intratracheal, oral, or intranasal administration, or by parenteral administration), or it may be formed in the subject receiving treatment after administration of a polynucleotide (vector) construct encoding a double-stranded RNA (dsRNA) molecule capable of forming an inhibitory RNA molecule. Those skilled in the art will be familiar with the various methods known in the art for formulating inhibitory RNA molecules for administration (e.g., in liposomes, nanoparticles, etc.). The present invention relates to the administration of a casein kinase 1 inhibitor and a pharmaceutical for the above-mentioned target disease indication, including administration in which one or both are administered by inhalation or are formulated for oral administration.

[0177] Although this invention is applied to humans, it is also useful for veterinary purposes for treatment. This invention is useful for domesticated animals or livestock such as cattle, sheep, horses, and poultry; companion animals such as cats and dogs; and zoo animals.

[0178] In this specification, “subject” refers to animals such as mammals or birds, including humans, monkeys, horses, dairy cows, sheep, goats, dogs, cats, guinea pigs, rats, mice, and chickens.

[0179] In another embodiment, the present invention provides a kit or product comprising a compound of formula (I) described herein or a pharmaceutical composition comprising a compound of formula (I).

[0180] In other embodiments, a kit is provided for use in therapeutic or prophylactic applications as described herein, comprising a container for containing a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I); and a label or accompanying document with instructions for use.

[0181] In another embodiment, the present invention provides a kit or product comprising a compound of formula (Ia) described herein or a pharmaceutical composition comprising a compound of formula (Ia).

[0182] In other embodiments, a kit is provided for use in therapeutic or prophylactic applications as referred to herein, comprising a container for containing a compound of formula (Ia) or a pharmaceutical composition comprising a compound of formula (Ia); and a label or accompanying document with instructions for use.

[0183] A kit or “product” may include a container and labels or accompanying documents on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and blister packs. Containers may be formed from a variety of materials, such as glass or plastic. Containers may contain a compound or composition of formula (I) or formula (Ia) that is effective in treating a medical condition and may have a sterile access port (for example, the container may be a vial with a stopper that can be pierced by an intravenous fluid bag or a subcutaneous needle). Labels or accompanying documents indicate that the composition is used for the treatment of a disorder. In one embodiment, the label or accompanying documents include instructions for use and indicate that a therapeutic or prophylactic composition can be used to treat the disorders described herein.

[0184] The kit may comprise (a) a therapeutic or prophylactic composition; and (b) a second container containing a second active ingredient or component. The kit in this embodiment of the present invention may further comprise a document indicating that the composition and other active ingredients can be used to treat a disorder or to prevent complications arising from the disorders described herein. Alternatively, the kit may further comprise a second (or third) container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0185] In certain embodiments, the therapeutic composition may be provided in the form of a disposable or reusable device comprising a compound of formula (I) or formula (Ia), or a therapeutic or prophylactic pharmaceutical composition containing a compound of formula (I) or formula (Ia). In one embodiment, the device is a syringe. The therapeutic or prophylactic composition may be provided in the device either ready for immediate use or requiring further mixing or addition of components. [Examples]

[0186] In vitro assay The primary assay for the activity of novel CK1δ / ε inhibitors involves the regulation of gene expression in BEAS-2B airway epithelial cells. The assay is performed under several conditions. Generally, TGF-β or TNF-α are used to elicit fibrillation or inflammation genes, respectively. The drug is added at a concentration of 10 μM or the indicated concentration for 30 minutes, then TGF-β / TNF-α is added and incubated for a further 20 hours. In some glucocorticoid experiments, dexamethasone (Dex, 30 nM) is added for the last 4 hours of the experiment, and then intracellular RNA is collected and the mRNA levels of inflammation and fibrillation marker genes are measured by RT-qPCR. Inhaled corticosteroids (ICS), budesonide, are also used in some experiments. Furthermore, the supernatant is collected in selected experiments at the end of the incubation period, and the levels of CSF-2 or IL-8 are measured by ELISA as described in (Tran et al. (2005) British Journal of Pharmacology, 145, 123-131).

[0187] The selected potential candidates were also assayed in A549 alveolar epithelial cells, a cell model commonly used in epithelial-mesenchymal transition (EMT) studies. The drugs were added at the indicated concentrations 30 minutes prior to TGF-β addition, followed by incubation for a further 24 hours. Intracellular RNA was then collected to measure the regulation of EMT-related and fibrosis genes.

[0188] The data presented in Figures 1-7 and Tables 1-4 suggest that the novel compound SS9-010 exhibits surprisingly higher potency in epithelial cells than PF670462, which has a similarly broad spectral activity against TGF-β-mediated effects. This compound also possesses a higher cLogP than PF670462.

[0189] method cell culture A549 alveolar epithelial cells (ATCC, Manasas, VA, USA) were cultured in DMEM containing 5% (v / v) FCS, 15 mM HEPES, 0.2% (v / v) sodium bicarbonate, 2 mM L-glutamine, 1% (v / v) non-essential amino acids, 1% (v / v) sodium pyruvate, 5 IU / mL penicillin, and 50 μg / mL streptomycin, as previously described (S. Salem, T. Harris, J. Mok Shiueh Lian, M. Yuen Sin Li, CRKeenan, MJS Chuliga, and AGS Stewart (2012), Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. Br J Pharmacol. 166:2036-2048).

[0190] Prior to the experiment, BEAS-2B and A549 cells were cultured in serum-free DMEM containing 0.25% bovine serum albumin (BSA) and an insulin-transferrin-selenium supplement (Monomed A; CSL, Parkville, Melbourne, Australia). Where indicated, cells were treated with one of a series of synthetic compounds (0.3–10 μM) and then exposed to 100 pM TGF-β1 (R&D Systems, Minneapolis, MN) or 300 pM bFGF (Promega, Madison, WI).

[0191] Analysis of gene expression Total RNA was extracted from cultured cells using the illustra RNAspin Mini RNA Isolation Kit (GE Healthcare). The RNA extract was reverse transcribed into cDNA using the High-Capacity RNA-to-cDNA Kit (Applied Biosystems). Real-time PCR was then performed using the QuantStudio 6 Flex Real-Time PCR System with iTaq Universal SYBR green supermix and the following thermal protocol: 50°C (2 min), 95°C (10 min), followed by 40 cycles at 95°C (15 sec), 60°C (1 min). The threshold cycle (CT) values ​​measured for the target gene were normalized against those obtained with 18S ribosomal RNA (18S rRNA) included as an internal control. The generation of specific PCR products was confirmed by dissociation curve analysis.

[0192] Immunofluorescence A549 cells for immunofluorescence staining were seeded on ibiTreat 8-chamber slides (ibidi) and allowed to adhere overnight. The cells were then serum-starved for 16 hours, pre-incubated with PF670462 (0.3–10 μM) for 30 minutes, and then pre-incubated with TGF-β (100 pM) for 48 hours. The cells were fixed in 10% neutral buffered formalin (Grale Scientific) for 15 minutes, and nonspecific binding sites were blocked by incubation in PBS with 5% normal goat serum / 0.3% Triton X-100 for 1 hour. E-cadherin expression was detected using a rabbit monoclonal antibody (Clone 24E10; catalog number 3195, Cell Signaling) followed by an AlexaFluor-488 conjugate anti-rabbit F(ab')2 fragment secondary antibody (catalog number 4412, Cell Signaling). Specific binding was confirmed using an isotype control antibody (Clone DA1E rabbit IgG; catalog number 3900, Cell Signaling). Cell nuclei were then stained with DAPI. Cells were imaged using a Leica SP5 confocal microscope (Biological Optical Microscopy Platform, University of Melbourne). Cell morphology and immunofluorescence staining were quantified using an Operetta High Content Imaging System (Biological Optical Microscopy Platform, University of Melbourne).

[0193] statistical analysis All data are expressed as mean ± SEM. Statistical comparisons between multiple groups were performed using Dunnett's post-hoc test for one-way ANOVA or Bonferroni's post-hoc test for two-way ANOVA. A p-value less than 0.05 was considered statistically significant.

[0194] Discussion of the results Figure 1 shows an assay in BEAS-B cells measuring the induction of SCNN1A, a glucocorticoid-regulated gene encoding the protein epithelial sodium channel alpha subunit, comparing the effect of SS9-010 with that of PF670462. Serum-starved BEAS-2B cells were treated with the CK1δ / ε inhibitor PF670462 (1, 3, 10 μM) or SS9-010 (1, 3, 10 μM) for 30 minutes, then treated with TGF-β1 (40 pM) for 24 hours, and subsequently stimulated with dexamethasone (30 nM) for 4 hours. RNA was then extracted and analyzed by RT-qPCR. Data are expressed as mean ± SEM for n=4 independent experiments. The potencies of PF670462 and SS9-010 were similar.

[0195] In the same experiment described in Figure 1, the expression of fibrogen plasminogen activator inhibitor-1 was measured (see Figure 2). The level of this gene was increased by both TGF-β and Dex, and they acted synergistically when added together. CK1 inhibitors, in a concentration-dependent manner, reduced the effects of each stimulus and further decreased baseline expression. Their potency in this effect was similar regardless of the conditions considered.

[0196] In a separate experiment, BEAS-2B cells were exposed to TNF-α with or without 30 minutes of pretreatment with either SS9-010 or PF670462 (1–10 μM). RNA was then extracted and analyzed by RT-qPCR. Each agent inhibited TNFα-stimulated PAI-1 expression with similar potency and maximum value (see Figure 3). Data are presented as mean ± SD for n=1 (3 technical replicates).

[0197] In serum-starved A549 cells, pretreatment with either PF670462 or SS9-010 (0.1–10 μM) followed by 24 hours of TGF-β (100 pM) treatment inhibited PAI-1 and CTGF expression in a concentration-dependent manner and restored the suppression of E-cadherin induced by TGF-β (100 pM). SS9-010 was significantly more potent than PF670462 in its effects on PAI-1 and ECad, as shown in Table 1 below, but not on CTGF.

[0198] Figure 5 shows the effect of the antifibrotic agent nintedanib for comparison with the degree and potency of PF670462. Serum-starved A549 cells were pre-treated with either PF670462 (0.1–10 μM) or nintedanib (0.01–1 μM), and then further treated with TGF-β (100 pM) for 24 hours. RNA was then extracted, and PAI-1, vimentin, and E-cadherin were measured by RT-qPCR. Data are expressed as mean ± SEM for n=4 independent experiments.

[0199] Figure 6 shows the effects of the CK1 inhibitors PF670462 and SS9-010 (1–10 μM) on the increase in TNF-α (10 ng / mL)-induced IL-8 expression and the level of immunoreactive IL-8 in the culture supernatant. Serum-starved BEAS-2B cells were pre-treated with either SS9-010 or PF670462 (1–10 μM) for 30 minutes, and then exposed to TNF-α (10 ng / mL) for a further 24 hours. RNA was extracted and measured by RT-qPCR. Inflammatory cytokines in the supernatant were measured by ELISA. Data are expressed as mean ± SEM for n=3 independent experiments. The effects of each CK1 inhibitor were maximized at the lowest concentration used in this assay, so no conclusions regarding relative efficacy can be drawn; however, both drugs are clearly active inhibitors of TNF-stimulated BEAS-2B cells.

[0200] Figure 7 shows the expression and levels of CSF-2 (GM-CSF) in the supernatant of the same experiment as depicted in Figure 6. In the case of CSF-2, there is a clear concentration-related decrease in the expression and protein levels of this colony-stimulating factor, but the two drugs appear to have no difference in efficacy.

[0201] Table 1 shows the relative potency of PF670462 and SS9-010 in regulating TGFβ-induced gene expression changes leading to epithelial-mesenchymal transition (EMT). EMT is a characteristic pathogenesis of fibrosis, associated with the metastasis and fibrosis of epithelial tumors in organs such as the heart, kidneys, liver, and lungs, and is known to be a cause of idiopathic pulmonary fibrosis (IPF), as well as a cause of fibrosis known to occur in asthma and COPD. SS9-010 shows significantly higher potency than PF670462 in attenuating the induction of fibrogen, plasminogen activator inhibitor-1 (PAI-1), and preventing the suppression of the E-cadherin gene, which encodes a protein involved in maintaining the barrier function and polarity of differentiated epithelial cells. The potency of PF670462 and SS9-010 in regulating CTGF induction is not statistically distinct. SS9-010 is significantly more potent in controlling the induction of Col1A, a gene encoding one of the major collagen tissue remodeling genes. The efficacy of these two drugs in controlling TGF-β-induced vimentin induction cannot be evaluated because the concentration-response relationship for PF670462 cannot be fitted. However, the effect of SS9-010 was significant at 3 μM, while PF670462 (3 μM) had no effect at all. All of these data represent the concentration-response relationship analysis shown in Figure 4.

[0202] [Table 1]

[0203] [Table 2]

[0204] [Table 3]

[0205] [Table 4]

[0206] In vivo experiment The relative activity of the drugs, as demonstrated in in vitro assays, will be further tested in a bleomycin model of pulmonary fibrosis.

[0207] A bleomycin model of pulmonary fibrosis All animal experiments were conducted in accordance with the ethical guidelines of the University of Melbourne Animal Ethics Committee (AEEC#1513736.1). As previously described (Langenbach et al., (2007). Can J Physiol Pharmacol, 85, 727-738), 6-8 week old, 20-25 g C57Bl / 6 mice (ARC, Perth, Australia) were treated with 35 μL of saline or bleomycin (105 mU per mouse) via intranasal administration on day 0. The effects of SS9-010 on pulmonary fibrosis in vivo were evaluated using acute and chronic bleomycin mouse models. SS9-010 was administered systemically by intraperitoneal injection or locally to the lungs for 15 minutes by inhalation of an aerosol generated using an oxygen concentrator connected to a Hudson nebulizer operating at 5 L / min. Mice that did not receive the SS9-010 treatment were administered a vehicle (10% DMSO, 90% peanut oil). Throughout the entire duration of the experiment, the mice were given food and water as needed. At the end of each experiment, bronchoalveolar lavage (BAL) was performed, the leukocyte cell types were enumerated, the cell-free protein levels were determined as previously described (Langenbach, et al., 2007), the lungs were dissected and rapidly frozen. Gene expression was determined from the fragmented frozen lung tissue.

[0208] BAL protein quantity measurement The total protein content in cell-free BAL solution was evaluated using the BioRad protein assay method.

[0209] BAL cell count measurement BAL cells in BAL fluid were stained with erythrosine B (EB) and manually counted using a hemocytometer. The total BAL cell count was calculated by accounting for the return volume of the BAL fluid.

[0210] Discussion of the results Figure 9 shows the effects of inhaled SS9-010 on bleomycin-induced BAL protein leakage, BAL cell recruitment, lung weight, and pulmonary fibrosis gene expression in mouse lungs. Female C57Bl / 6 mice were administered intranasally with either bleomycin or saline on day 0. SS9-010 was administered once daily for 15 minutes by inhalation of an aerosol produced by spraying at a concentration of 1 mg / mL from day -1 to day 3. Bronchoalveolar lavage (BAL) protein and BAL cell count were evaluated. Pulmonary fibrosis gene expression was also evaluated on day 3. Data are expressed as mean ± SEM (n=6). SS9-010 showed an effect on BAL protein and pulmonary fibrosis gene expression, as well as a moderate suppression of BAL cell count.

[0211] Figure 10 shows the effects of intraperitoneal injection of SS9-010 on bleomycin-induced BAL protein leakage, BAL cell recruitment, and pulmonary fibrosis gene expression in mouse lungs. Female C57Bl / 6 mice were administered bleomycin or saline intraperitoneally on day 0. SS9-010 (3 or 10 mg / kg / day, ip) was administered from day 1 to day 3. Bronchoalveolar lavage (BAL) protein and BAL cell count showed favorable trends. Pulmonary fibrosis gene expression was also evaluated on day 3. Data are expressed as mean ± SEM (n=4 saline, n=5 other groups). Systemic SS9-010 (3 or 10 mg / kg / day, ip) had no effect on BAL protein or BAL cell count. IL-6 induction was reduced by SS9-010 treatment, but arginase-1 induction was not.

[0212] In a study to confirm the effects of oral administration of either PF670462 or SS8-058, the inventors collected livers on day 3 from mice treated intranasally with bleomycin on day 0 and measured the gene expression of products involved in fibrosis. Mice were treated once daily from day 1 to day 3 by forced oral administration with either PF670462 or SS8-058 (30 mg / kg, po). Each treatment significantly reduced the respective levels of fibrosis genes.

[0213] Measurement of airway hyperresponsiveness in vivo Acute ovalbumin-induced asthma model: BALB / c mice were sensitized by intraperitoneal injection with a combination of ovalbumin (50 μg), aluminum hydroxide (20 mg / mL adjuvant), and physiological saline. 200 μL of the ovalbumin mixture was administered to each mouse on day 0, followed by repeated intraperitoneal injection using a 22-gauge needle on day 14. From days 21 to 28, mice were exposed daily to 1% aerosolized ovalbumin in physiological saline at a rate of 2 ml / min for 30 minutes using a deVilbiss nebulizer. SS9-010 was administered topically to the lungs for 15 minutes from days 21 to 28 by inhalation of an aerosol generated using an oxygen concentrator connected to a Hudson nebulizer operating at 5 L / min. The estimated cumulative dose was 1 μg.

[0214] Pulmonary function measurement: Pulmonary function was measured using a modified low-frequency forced oscillation method and a small animal ventilator (flexiVent; Scireq, Montreal, QC, Canada) as previously described (Bozanich et al., (2008) Respir Physiol Neurobiol, 162, 190-196). On the day of necropsy, mice were anesthetized with ketamine and xylazine and placed on the pulmonary function testing device (FlexiVent). To measure airway hyperresponsiveness, mice were administered methacholine via aerosol through a tracheal cannula in a dose range of 0.1–30 mg / ml for 5 minutes. Pulmonary function was performed as a terminal procedure; each mouse was deeply anesthetized intraperitoneally with a 27-gauge needle using a combination of ketamine (150 mg / kg) and xylazine (15 mg / kg) in physiological saline. Once anesthesia was achieved, a 2 cm long surgical incision was made using a scalpel in a distal cutting motion through the subcutaneous tissue to the anterior tracheal muscle layer. Using blunt dissection, the peritracheal muscle layer was cut longitudinally to expose the trachea. A 1 cm long, 1.27 mm endotracheal tube was inserted into the trachea and secured with silk sutures, and the mouse was ventilated with flexiVent. The mouse was placed on the SCIREQ FlexiVent system, ventilated, and lung function was measured at a constant respiratory rate (150 breaths per minute) with the tracheal cannula connected to the system. The respiratory mechanism was evaluated in one mouse for approximately 60 minutes. Airway hyperresponsiveness was established by administering increasing doses of methacholine to the mouse either via an endotracheal cannula or aerosol. Respiratory impedance (Z) rs We measured the following, and as previously described (Larcombe et al., (2011) Influenza Other Respir Viruses, 5, 334-342), we separated them into airway and parenchymal components to enable the calculation of Newton resistance (Rn, equal to airway resistance (Raw) due to high compliance of the chest wall), tissue dumping (G), and elastance (H).

[0215] Discussion of the results Figure 12 shows airway hyperresponsiveness (AHR) in response to inhaled metacholine (MCh), measured in sham- or ovalbumin (OVA)-sensitized BALB / c mice that received inhalation of SS9-010 (estimated deposition dose of 1 μg) or saline. Resistance (Rn), representing the level of pulmonary contraction, was assessed. Elastance (E) represents the elastic stiffness of the respiratory system at ventilation frequency. Compliance (C) describes the ease with which the respiratory system expands. Data are expressed as mean ± SEM (n=6). The data showed a significant increase in central airway resistance (Rn) and elastance in OVA-exposed mice. This induction was attenuated in mice treated with SS9-010. No significant difference was observed in compliance changes between the OVA / SS9-010 group and the OVA-only group.

[0216] synthesis General Proton nuclear magnetic resonance spectrum ( 1 ¹H NMR (400, 600 MHz) and proton decoupled carbon-13 nuclear magnetic resonance spectra ( 13 ¹³C NMR (100, 150 MHz) was obtained in a deuterated solvent using the residual proton solvent as an internal standard. Following the chemical shift, multiplicity, coupling constant (J, Hz), integration, and assignment were performed where possible. Flash chromatography was performed using an automated system according to the procedure of Still et al. 1 Thin-layer chromatography (TLC) for analysis is performed on 2mm thick silica gel with an aluminum backing, 60 GF. 254 The procedure was carried out, and the chromatogram was visualized under an ultraviolet lamp. High-resolution mass spectra (HRMS) were obtained by ionizing the sample using electrospray ionization (ESI) and time-of-flight mass spectrometer. Dry THF and CH2Cl2 were obtained using the method of Pangborn et al. 2 The results were obtained by [method / method]. Pet.spirits refers to petroleum ether with a boiling point range of 40–60°C. All other commercially available reagents were used as received.

[0217] [C5]

[0218] Benzyl 4-(dimethoxymethyl)pyrimidine-2-ylcarbamate (1) A solution of benzyl chloroformate (2.57 ml, 18.1 mmol) in CH2Cl2 (2.5 ml) was added to a mixture of 4-dimethoxymethylpyrimidine-2-ylamine (0.330 g, 1.95 mmol) and pyridine (0.2 ml) in CH2Cl2 (7.5 ml) at -18°C. The solution was gradually warmed to room temperature and stirred overnight. TLC of the reaction mixture showed that the starting materials were not completely consumed. Therefore, the reaction mixture was cooled again to -18°C and an additional benzyl chloroformate (0.250 ml, 1.81 mmol) was added. The reaction mixture was diluted with CH2Cl2, washed with water, dried in (MgSO4), filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 2:1) gave 1 as a white solid (0.496 g, 84%). 1 H NMR(CDCl3,400MHz)δ 3.39(2×3H,s),5.21(1H,s),5.24(2H,s),7.17(1H,d,J=5.2Hz),7.32-7.41(5H,m),8.33(1H,br s),8.63(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 54.0,67.5,102.5,113.4,128.5,128.6,128.7,135.8,151.5,157.4,159.3,167.0;HRMS(ESI + ) Calculated value C 15 H 18 N3O4(M+H)304.1297. Measured value: 304.1292.

[0219] Benzyl 4-formylpyrimidine-2-ylcarbamate hydrochloride (2) A 4M aqueous solution (2 ml) was added to a 1 ml solution of 1 ml (0.350 g, 1.15 mmol) of THF. The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0220] Benzyl(4-(((1-benzylpiperidine-4-yl)imino)-methyl)piperidine-2-yl)carbamate(3) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.290 g, 1.12 mmol) in an HCl aqueous solution (2 ml, 7.90 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.158 g, 1.14 mmol) were added, followed by 4-amino-1-benzylpiperidine (0.141 g, 0.838 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1 ¹H NMR analysis showed that approximately 10% of the aldehyde remained, so an additional amount of 4-amino-1-benzylpiperidine (0.035 g, 0.025 mmol) was added, and stirring was continued for another hour. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The crude material was used in the next step without purification (0.450 g, 94%). 1 H NMR(CDCl3,400MHz)δ 1.71-1.74(2H,m),1.83-1.93(2H,m),2.13-2.18(2H,m),2.92-2.95(2H,m),3.33 -3.38(1H,m),5.25(2H,s),7.30-7.43(10H,m),7.59(1H,d,J=5.2Hz),8.26(1H,br s),8.61(1H,d,J=4.8Hz); 13 C NMR(CDCl3,100MHz)δ 33.2,51.9,63.2,67.6,112.6,127.2,128.4,128.6,128.7,128.8,129.3,135.7,151.5,157.7,158.7,159.1,163.0 + ) Calculated value C 25 H 28 N5O2(M+H) 430.2243. Measured value 430.2239.

[0221] Benzyl(4-(1-(1-benzylpiperidine-4-yl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(4) α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.262 g, 0.905 mmol) and 20% K2CO3 aqueous solution (0.250 g, 1.808 mmol) were added to imine 3 (0.350 g, 0.815 mmol) in a CH2Cl2 solution at 20°C, while stirring was continued overnight. At this point, additional imine (0.038 g, 0.091 mmol) and K2CO3 (0.090 g, 0.651 mmol) were added, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (MeOH / Âde 1:4) yielded 4 as a pale yellow solid (0.345 g, 59%). 1 H NMR(DMSO-d6,400MHz)δ 1.91-1.94(4H,m),2.01-2.08(2H,m),2.82(2H,br d,J=10.8Hz),3.45(2H,s),4.84-4.88(1H,m),5.20(2H,s),6.86(1H,d,J=5.2Hz),7. 13-7.17(2H,m),7.22-7.45(2H,m),8.14(1H,s),8.51(1H,d,J=5.2Hz),10.73(1H,s); 13 C NMR(DMSO-d6,100MHz)δ 32.8,52.0,53.1,61.9,65.8,115.2,116.4,124.0,126.9,127.9,129.0,128.1,128.4,128 .8,129.9,13.09,136.6,137.3,138.5,141.2,151.8,157.9,158.2,158.6,161.5;HRMS(ESI + ) Calculated value C 32 H 32 FN6O2(M+H) 563.2571. Measured value 563.2565.

[0222] 4-(4-(4-fluorophenyl)-1-(piperidine-4-yl)-1H-imidazole-5-yl)pyrimidine-2-amine(5) 10% Pd / C (0.1 g) and ammonium formate (0.390 g, 6.22 mmol) were added to a solution of 4 (0.350 g, 0.622 mmol) methanol (5 ml). The resulting reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to yield a residue, which was used without purification (0.206 g, 98%). 1 H NMR(MeOH-d4,400MHz)δ 2.08-2.17(2H,m),2.37-2.40(2H,m),3.02-3.09(2H,m),3.41-3.47(2H,m),4.85-4.94(1H,m),6.40(1H ,d,J=5.2Hz),7.06-7.11(2H,m),7.39-7.43(2H,m),8.03(1H,s),8.12(1H,d,J=5.2Hz),8.53(1H,s,NH); 13 C NMR(MeOH-d4,100MHz)δ 27.6,28.3,36.3,36.5,40.6,42.9,59.7,113.3,115.3,115.5,129.9,1 30.0,135.5,142.2,151.6,158.6,159.7,161.2,163.2,163.7;HRMS(ESI + ) Calculated value C 18 H 20 FN6(M+H) 339.1733. Measured value 339.1731.

[0223] Octanal (6) A solution of 1-octanol (0.50 g, 3.83 mmol) in CH2Cl2 (5 ml) was added dropwise to a stirred suspension of pyridinium dichromate (2.16 g, 5.75 mmol) and Celite (0.5 g) in CH2Cl2 (5 ml). The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and the resulting crude product was purified by flash chromatography (siRNA / petroleum ether 1:9) to give compound 6 as a colorless oil (0.350 g, 71%). 1 H NMR(CDCl3,400MHz)δ 0.88(3H,t,J=8Hz),1.20-1.30(8H,m),1.59-1.64(2H,m),2.41(2H,t,J=8Hz),9.76(1H,s).

[0224] 4-Phenyl-1-butanal(8) Dess-Martin periodinane (1.69 g, 3.98 mmol) was added to a solution of 4-phenyl-1-butanol (0.50 g, 3.32 mmol) in CH2Cl2 (10 ml) at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes, followed by stirring at room temperature for 1.5 hours. The reaction mixture was quenched with 10% sodium thiosulfate (50 ml), and the product was extracted into CH2Cl2. The organic layer was separated, washed with 1 M aqueous NaOH (50 ml), followed by washing with water (50 ml), dried (Na2SO4), filtered, and concentrated. The crude substance was used directly in the next reaction (0.485 g, 98%). 1 H NMR(CDCl3,400MHz)δ 1.93-2.01(2H,pent,J=7.6Hz),2.46(2H,td,J=1.2,7.2Hz),2.66(2H,t,J=8Hz),7.17-7.22(2H,m),7.26-7.31(3H,m),9.76(1H,t,J=1.2Hz); 13 C NMR(CDCl3,100MHz)δ 23.8,35.2,43.3,126.2,128.4,128.6,141.3,202.5.

[0225] [C6]

[0226] 4-(4-(4-fluorophenyl)-1-[1-octylpiperidine-4-yl]-1H-imidazole-5-yl)pyrimidine-2-amine (7;SS8-058) Octanal 6 (0.133 g, 1.04 mmol) was added to a solution of Octanal 5 (0.250 g, 0.739 mmol) in dry THF (5 ml). The resulting reaction mixture was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (0.454 g, 2.14 mmol) was added, and the mixture was cooled, maintaining a temperature below 37°C. After stirring for 2 hours, the TLC showed the presence of approximately 40% amine. Therefore, additional aldehyde 6 (0.095 g, 0.721 mmol) and sodium triacetoxyborohydride (0.313 g, 1.42 mmol) were added, and stirring was continued overnight. The reaction mixture was slowly quenched with saturated aqueous NaHCO3, followed by dilution with siRNA. The organic layer was separated, washed with water, dried (MgSO4), filtered, and concentrated. Flash chromatography of the residue (MeOH / siRNA / Et3N 6:93:1) yielded 7 as a pale yellow solid (0.145 g, 44%). 1 H NMR(CDCl3,400MHz)δ 0.88(3H,t,J=6.8Hz),1.21-1.36(10H,m),1.49-1.68(2H,m),2.01-2.11(4 H,m),2.33-2.37(2H,m),3.05-3.06(2H,m),4.50-4.57(1H,m),5.08(2H,br s),6.50(1H,d,J=4.8Hz),6.97-7.02(2H,m),7.43-7.46(2H,m),7.77(1H,s),8.18(1H,d,J=5.2Hz); 13 C NMR(CDCl3,150MHz)δ 14.3,22.8,27.4,27.8,29.4,29.7,32.0,33.7,53.2,54.3,58.7,113.1,115.4,115.6,124. 9,130.06,130.12,130.7,136.0,138.9,142.1,158.7,159.4,161.5,163.1,163.5;HRMS(ESI + ) Calculated value C 26 H 36 FN6(M+H) 451.2985. Measured value: 451.2978.

[0227] 4-(4-(4-fluorophenyl)-1-[1-(4-phenylbutyl)piperidine-4-yl)-1H-imidazole-5-yl)pyrimidine-2-amine(9;SS8-070) A mixture of 4-phenyl-1-butanal 8 (0.061 g, 0.404 mmol) and 5 (0.10 g, 0.296 mmol) in dry THF (5 ml) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (0.182 g, 0.859 mmol) was added, and the mixture was cooled, maintaining a temperature below 37°C. Stirring was continued for 2 hours, at which point TLC showed the presence of approximately 50% amine. Therefore, additional aldehyde 8 (0.043 g, 0.289 mmol) and sodium triacetoxyborohydride (0.090 g, 0.429 mmol) were added, and stirring was continued overnight. The reaction mixture was slowly quenched with saturated aqueous NaHCO3, followed by dilution with ELISA. The organic layer was separated, washed with water, dried (MgSO4), filtered, and concentrated. Flash chromatography of the residue (MeOH / siRNA / Et3N 5:94:1) yielded 9 as a white solid (0.028 g, 40%). 1 1H NMR (CDCl3, 400MHz) δ 1 H NMR(CDCl3,400MHz)δ 1.24-1.27(4H,m),1.50-1.68(4H,m),1.99-2.11(2H,m),2.36-2.40(2H,t,J=8H z),2.62-2.65(2H,t,J=8Hz),3.02-3.04(2H,m),4.49-4.58(1H,m),5.06(2H,br s),6.50(1H,d,J=4.8Hz),6.97-7.02(2H,m),7.17-7.19(3H,m),7.26-7.29(2H,m),7.43-7.46(2H,m),7.76(1H,s),8.18(1H,d,J=4.8Hz); 13C NMR(CDCl3,100MHz)δ 27.0,29.5,29.9,33.6,35.9,53.2,54.2,58.4,113.1,115.4,115.6,124.8,125.9,128.45,128 .53,130.07,130.13,130.6,136.0,142.2,142.5,158.7,159.3,161.5,163.1,163.5;HRMS(ESI + ) Calculated value C 28 H 32 FN6(M+H) 471.2672. Measured value 472.2681.

[0228] [C7]

[0229] 4-(1-(1-butylpiperidine-4-yl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(10;SS8-074) A mixture of 1-bromobutane (0.020 g, 0.147 mmol), 5 (0.050 g, 0.147 mmol), and cesium carbonate (0.192 g, 0.589 mmol) in THF (3 ml) and water (1 ml) was heated to 70°C and stirred overnight. When TLC showed the presence of approximately 50% amine, additional 1-bromobutane (0.020 g, 0.147 mmol) and cesium carbonate (0.96 g, 0.295 mmol) were added, and stirring was continued overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried, filtered, and concentrated. Flash chromatography of the residue (MeOH / ethyl acetate / Et3N 5:94:1) yielded 10 as a white solid (0.028 g, 56%). 1 H NMR(CDCl3,400MHz)δ 0.92(3H,t,J=7.2Hz),1.25-1.37(4H,m),1.42-1.53(2H,m),2.03-2.11(4 H,m),2.36-2.40(2H,m),3.06-3.08(2H,m),4.50-4.61(1H,m),5.12(2H,br s),6.50(1H,d,J=5.2Hz),6.97-7.01(2H,m),7.42-7.46(2H,m),7.77(1H,s),8.18(1H,d,J=4.8Hz);13 C NMR(CDCl3,150MHz)δ 14.2,21.0,29.9,33.5,53.2,54.1,58.3,113.1,115.4,115.6,124.8,130.0 6,130.13,130.6,136.0,142.2,158.7,159.3,161.5,163.1,163.5;HRMS(ESI + ) Calculated value C 22 H 28 FN6(M+H) 395.2359. Measured value: 395.2348.

[0230] 4-(1-(1-dodecylpiperidine-4-yl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(11;SS8-070) A mixture of 1-bromododecane (0.043 g, 0.147 mmol), 5 (0.050 g, 0.147 mmol), and cesium carbonate (0.192 g, 0.589 mmol) in THF (3 ml) and water (1 ml) was heated to 70°C and stirred overnight. When TLC showed the presence of approximately 10% amine, additional 1-bromododecane (0.008 g, 0.029 mmol) and cesium carbonate (0.025 g, 0.074 mmol) were added, and stirring was continued for 3 hours. The reaction mixture was diluted with siRNA, washed with water and brine, dried, filtered, and concentrated. Flash chromatography of the residue (MeOH / siRNA / Et3N 5:94:1) gave 11 as a white solid (0.031 g, 40%). 1 H NMR(CDCl3,400MHz)δ 0.88(3H,t,J=7.2Hz),1.09-1.28(18H,m),1.42-1.49(2H,m),1.96-2.15(4H,m),2.35-2.38(2H,m),3.04-3.11(2H,m),4.51 -4.59(1H,m),5.07(2H,s),6.50(1H,d,J=5.2Hz),6.97-7.01(2H,m),7.43-7.46(2H,m),7.77(1H,s),8.18(1H,d,J=5.2Hz); 13C NMR(CDCl3,150MHz)δ 14.3,22.9,27.4,27.8,29.5,29.7,29.78,29.80,29.83,32.1,33.7,52.2,52.3,58.7,113.1,115. 4,115.6,124.9,130.06,130.13,130.6,136.0,142.1,158.7,159.4,161.5,163.1,163.5;HRMS(ESI + ) Calculated value C 30 H 44 FN6(M+H) 507.3611. Measured value 507.3613.

[0231] [C8]

[0232] Benzyl(4-((cyclohexylimino)-methyl)pyrimidine-2-yl)carbamate(12) A 45% KOH aqueous solution (0.88 g, 15.8 mmol) was added to an ice-cold solution of crude aldehyde 2 (1.4 g, 5.44 mmol) in an HCl aqueous solution (4 ml, 15.8 mmol) while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.76 g, 5.44 mmol) were added, followed by cyclohexylamine (0.63 g, 6.36 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1 ¹H NMR analysis showed that approximately 20% of the aldehyde remained, so additional cyclohexylamine (0.06 g, 0.63 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The resulting crude material was used in the next step without purification (1.59 g, 85%). 1 H NMR(CDCl3,400MHz)δ 1.24-1.42(4H,m),1.51-1.60(2H,m),1.67-1.85(4H,m),3.28-3.34(1H,m),5.25(2H,s, CH2Ph),7.34-7.42(5H,m),7.54(1H,d,J=4.8Hz),8.25(1H,s,NH),8.56(1H,d,J=5.2Hz); 13C NMR(CDCl3,100MHz)δ 24.6,25.6,34.0,67.6,69.8,112.4,128.6,128.7,128.8,135.7,151.6,157.8,158.2,158.9,163.2;HRMS(ESI + ) Calculated value C 19 H 23 N4O2(M+H) 339.1821. Measured value 339.1817.

[0233] Benzyl(4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(13) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (1.42 g, 4.90 mmol), imine 12 (1.5 g, 4.43 mmol), and a 20% K2CO3 aqueous solution (1.35 g, 9.77 mmol) in CH2Cl2 at 20°C was stirred overnight. At this point, additional imine (0.14 g, 0.49 mmol) and K2CO3 (0.34 g, 1.04 mmol) were added, and the reaction mixture was stirred a second time overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 6:4) yielded 13 as a white solid (1.62 g, 77%). 1 H NMR(CDCl3,400MHz)δ 1.20-1.28(2H,m),1.38-1.47(2H,m),1.55-1.65(2H,m),1.71-1.85(2H,m),2.10-2.13(2H,m),5.04-5.11 (1H,m),5.26(2H,s),6.76(1H,d,J=5.2Hz),6.99-7.04(2H,m),7.34-7.45(7H,m),7.78(1H,s),8.06(1H,br s,NH),8.33(1H,d,J=5.2Hz); 13C NMR(CDCl3,100MHz)δ 25.6,34.7,55.5,67.6,115.6,115.8,116.7,124.1,128.7,128.8,130.4,130.56,13 0.8,133.0,135.8,136.8,143.8,151.2,157.5,158.2,159.5,161.4,163.9;HRMS(ESI + ) Calculated value C 27 H 27 FN5O2(M+H) 472.2149. Measured value 472.2150

[0234] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine hydrochloride (14; PF670462) A mixture of 13 (0.30 g, 0.64 mmol) and 20 wt% Pd(OH)2 / C (0.13 g) in THF (5 ml) and methanol (0.5 ml) was hydrogenated at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product, which was stirred in 4 M aqueous HCl (2 ml) and methanol (2 ml) for 1 hour to give the HCl salt. After evaporation of the solvent, recrystallization from a combination of methanol, acetone, and petroleum ether gave 14 as a white solid (0.19 g, 83%). 1 H NMR(MeOH-d4,400MHz)δ 1.28-1.40(2H,m),1.48-1.58(2H,m),1.78-1.88(2H,m),1.94-1.98(2H,m),2.27-2.30(2H,m),4.95-5. 02(1H,m),6.67(1H,d,J=6.4Hz),7.29-7.33(2H,m),7.59-7.62(2H,m),8.26(1H,d,J=6Hz),9.48(1H,s); 13 C NMR(MeOH-d4,100MHz)δ 24.6,25.1,33.4,59.1,110.4,116.3,116.6,121.8,121.9,124.6,136.1,136.2,148.1,156.3,162.7,163.1,165.6 + ) Calculated value C 19 H 21FN5(M+H) 338.1781. Measured value 339.1778.

[0235] Benzyl(4-((adamantan-1-ylimino)-methyl)pyrimidine-2-yl)carbamate(15) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.250 g, 0.972 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol) while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.158 g, 1.14 mmol) were added, followed by 1-adamantylamine (0.175 g, 1.17 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1 ¹H NMR analysis showed that approximately 20% of the aldehyde remained, so an additional 1-adamantylamine (0.030 g, 0.19 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The crude material was used in the next step without purification (0.36 g, 94%). 1 H NMR(CDCl3,400MHz)δ 1.57-1.79(12H,m),2.01-2.08(3H,m),5.26(2H,s),7.34-7.43(5H,m),7.61(1H,d,J=4.8Hz),8.18(1H,br s,NH),8.57(1H,d,J=4.8Hz); 13 C NMR(CDCl3,100MHz)δ 29.4,36.4,42.7,59.2,67.4,112.1,128.4,128.5,128.6,135.6,151.4,157.5,158.6,163.7;HRMS(ESI + ) Calculated value C 23 H 27 N4O2(M+H) 391.4867. Measured value 391.4872.

[0236] Benzyl(4-(adamantan-1-yl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(16) α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.300 g, 1.04 mmol) and 20% K2CO3 aqueous solution (0.286 g, 2.07 mmol) were added to a solution of imine 15 (0.363 g, 0.936 mmol) in CH2Cl2 at 20°C, and the mixture was stirred overnight. At this point, additional imine (0.036 g, 0.094 mmol) and K2CO3 (0.143 g, 1.03 mmol) were added, and the reaction mixture was stirred a second time overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 39:60:1) followed by recrystallization using CH3CN / H2O gave 16 as a white solid (0.070 g, 15%). 1 H NMR(CDCl3,400MHz)δ 1.57-1.70(7H,m),2.10-2.17(3H,m),2.18-2.23(5H,m),5.26(2H,s),6.79(1H,d ,J=4.8Hz),6.88-6.92(2H,m),7.20-7.26(2H,m),7.35-7.46(5H,m),7.73(1H,br s,NH),7.80(1H,s),8.50(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ HRMS(ESI + ) Calculated value C 31 H 31 FN5O2(M+H) 524.2462. Measured value 524.2457.

[0237] 4-(adamantan-1-yl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine (17; SS8-122) A mixture of 16 (0.06 g, 0.15 mmol) and 20 wt% Pd(OH)2 / C (0.20 g) in THF (5 ml) and methanol (0.5 ml) was treated with hydrogen at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 5:94:1) gave 17 as a white solid (0.038 g, 86%). 1 H NMR(CDCl3,400MHz)δ 1.60-1.72(7H,m),2.12-2.24(8H,m),5.16(2H,br s),6.52(1H,d,J=5.2Hz),6.89-6.94(2H,m),7.26-7.33(2H,m),7.77(1H,s),8.24(1H,d,J=4.8Hz); 13 C NMR(CDCl3,150MHz)δ HRMS(ESI + ) Calculated value C 23 H 25 FN5(M+H) 390.2094. Measured value 391.2102.

[0238] Benzyl(4-((cycloheptylimino)-methyl)pyrimidine-2-yl)carbamate(18) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.250 g, 0.972 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol) while maintaining the temperature below 15°C. To the resulting neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.158 g, 1.14 mmol) were added, followed by cycloheptylamine (0.132 g, 1.16 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1¹H NMR analysis showed that approximately 20% of the aldehyde remained, so additional cycloheptylamine (0.015 g, 0.19 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The resulting crude product was used in the next step without purification (0.31 g, 91%). 1 H NMR(CDCl3,400MHz)δ 1.50-1.80(12H,m),3.45-3.48(1H,m),5.25(2H,s,CH2Ph),7.33-7.41(5H,m),7.54(1H,d,J=5.2Hz),8.20(1H,s,NH),8.54(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 24.7,28.6,36.0,67.5,72.3,112.4,128.6,128.7,128.8,135.7,151.7,157.4,157.9,158.8,163.3;HRMS(ESI + ) Calculated value C 20 H 25 N4O2(M+H) 353.1978. Measured value 353.1981.

[0239] Benzyl(4-(1-cycloheptyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(19) α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.250 g, 0.861 mmol) and 20% K2CO3 aqueous solution (0.238 g, 1.73 mmol) were added to the solution of imine 18 (0.274 g, 0.778 mmol) in CH2Cl2 at 20°C, while stirring was continued overnight. At this point, additional imine (0.027 g, 0.078 mmol) and K2CO3 (0.119 g, 0.865 mmol) were added, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried in (MgSO4), filtered, and concentrated. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 6:93:1) gave 19 as a white solid (0.24 g, 70%). 1H NMR(CDCl3,400MHz)δ 1.52-1.87(10H,m),2.14-2.18(2H,m),5.24-5.30(1H,m),5.26(2H,s),6.74(1H,d,J=5.2Hz ),6.99-7.03(2H,m),7.33-7.44(7H,m),7.77(1H,s),8.31(1H,d,J=5.2Hz),8.38(1H,s,NH); 13 C NMR(CDCl3,100MHz)δ 24.7,27.5,36.7,57.5,67.7,115.5,115.7,116.7,124.0,128.7,128.77,128.80,130.4 ,130.5,130.8,135.8,137.1,143.6,151.3,157.6,158.1,159.6,161.4,163.9;HRMS(ESI + ) Calculated value C 28 H 28 FN5O2(M+H) 485.2227. Measured value 486.2235.

[0240] 4-(1-cycloheptyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine (20; SS8-138) A mixture of 19 (0.235 g, 0.485 mmol) and 20 wt% Pd(OH)2 / C (0.25 g) in THF (5 ml) and methanol (0.5 ml) was treated with hydrogen at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 5:94:1) gave 20 as a white solid (0.155 g, 92%). 1 H NMR(CDCl3,400MHz)δ 1.44-1.90(10H,m),2.16-2.21(2H,m),4.64-4.71(1H,m),5.06(2H,br s),6.50(1H,d,J=5.2Hz),6.97-7.01(2H,m),7.43-7.46(2H,m),7.73(1H,s),8.19(1H,d,J=5.2Hz); 13C NMR(CDCl3,150MHz)δ HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 352.1937. Measured value: 352.1934.

[0241] Benzyl(4-((exo-2-aminonorbornane)-methyl)pyrimidine-2-yl)carbamate(21) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.250 g, 0.972 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.158 g, 1.14 mmol) were added, followed by exo-2-aminonorbornane (0.129 g, 1.16 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1 1H NMR showed complete consumption of the aldehyde. The reaction mixture was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered, and concentrated. The resulting crude product was used in the next step without further purification (0.24 g, 71%). 1 H NMR(CDCl3,400MHz)1.20-1.27(3H,m),1.45-1.64(4H,m),1.85-1.88(1H,m),2.12-2.19(1H,m),2.29-2.38(1H,m) ,3.38-3.43(1H,m),5.25(2H,m),7.35-7.41(5H,m),7.54(1H,d,J=5.2Hz),8.16(1H,s,NH),8.55(1H,d,J=5.2Hz); 13C NMR(CDCl3,100MHz)δ HRMS(ESI + ) Calculated value C 20 H 23 N4O2(M+H) 351.1821. Measured value 351.1815.

[0242] Benzyl(4-(1-(exo-2-aminonorbornane)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(22) α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.200 g, 0.691 mmol) and 20% K2CO3 aqueous solution (0.191 g, 1.38 mmol) were added to a solution of imine 21 (0.218 g, 0.622 mmol) in CH2Cl2 (5 ml) at 20°C, while stirring was continued overnight. At this point, additional imine (0.024 g, 0.062 mmol) and K2CO3 (0.047 g, 0.345 mmol) were added, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried in (MgSO4), filtered, and concentrated. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 6:93:1) followed by recrystallization using CH3OH / CH2Cl2 yielded 22 as a white solid (0.071 g, 23%). 1 H NMR(CDCl3,400MHz)δ 1.18-1.23(1H,m),1.35-1.43(2H,m),1.51-1.68(4H,m),1.76-1.81(1H,m),2.35-2.40(1H,m),2.61-2.63(1H,m),5.12-5.15(1H, m),5.20(2H,m),6.75(1H,d,J=5.2Hz),6.99-7.03(2H,m),7.34-7.45(7H,m),7.81(1H,s),8.04(1H,s,NH),8.33(1H,d,J=5.2Hz); 13C NMR(CDCl3,100MHz)δ 27.5,28.4,36.7,36.8,41.0,42.3,59.8,67.6,115.6,115.8,116.7,124.4,128.7,128.8 ,130.31,130.4,130.7,135.8,136.5,144.2,151.3,157.4,158.2,159.7,161.4;HRMS(ESI + ) Calculated value C 28 H 27 FN5O2(M+H) 484.2149. Measured value 484.2138.

[0243] 4-(1-(1-(Exo-2-aminonorbornane)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(23;SS8-154) A mixture of 22 (0.070 g, 0.147 mmol) and 20 wt% Pd(OH)2 / C (0.020 g) in THF (5 ml) and methanol (0.5 ml) was treated with hydrogen at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 5:94:1) gave 23 as a white solid (0.030 g, 60%). 1 H NMR(CDCl3,400MHz)δ 1.18-1.37(3H,m),1.53-1.82(5H,m),2.39-2.44(1H,m),2.56-2.61(1H,m),4.55-4.58(1H,m),5.10(2H,br s),6.51(1H,d,J=5.2Hz),6.96-7.01(2H,m),7.43-7.46(2H,m),7.76(1H,s),8.19(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 27.6,28.3,36.3,36.5,40.6,42.9,59.7,113.3,115.3,115.5,129.9,1 30.0,135.5,136.5,142.2,158.6,159.7,161.2,163.2,163.7;HRMS(ESI + ) Calculated value C 20 H 21FN5(M+H) 350.1781. Measured value: 350.1785.

[0244] Benzyl-(4-((methylimino)methyl)pyrimidine-2-yl)carbamate(24) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.137 g, 0.531 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.069 g, 0.502 mmol) were added, followed by a methylamine THF solution (530 μL, 1.06 mmol, 2.0 M). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 Since 1H NMR analysis indicated incomplete consumption of the aldehyde, additional methylamine (265 μL, 0.531 mmol) was added, and the reaction mixture was stirred for a further 2 hours. After complete consumption of the aldehyde, the crude material was used in the next step without isolation.

[0245] Benzyl(4-(4-(4-fluorophenyl)-1-methyl-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(25) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.184 g, 0.637 mmol), imine (0.144 g, 0.531 mmol), and 20% K2CO3 aqueous solution (0.440 mL, 0.637 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 3:2) yielded methyl carbamate as a colorless solid (79.2 mg, 37%) at mp190–198°C. 1H-NMR (500MHz; CDCl3):δ 4.03(3H,s),5.24(2H,s),6.67(1H,dt,J=5.3,0.7Hz),7.07-7.03(2H,m),7.46-7.31(7H,m),7.59(1H,s),8.16-8.14(1H,m),9.54(1H,s); 13 C-NMR (126MHz; CDCl3): δ 35.1,67.6,115.2,115.6,115.8,125.1,128.7,128.7,128.8,130.5(d,J C-F =8.1Hz),130.8(d,c=3.3Hz),135.6,141.1,144.5,151.6,151.6,157.4,157.7,158.8,162.8(d,J C-F= 248Hz).HRMS(ESI + ) Calculated value C 22 H 19 FN5O2(M+H) 404.1523. Measured value: 404.1518.

[0246] 4-(4-(4-fluorophenyl)-1-methyl-1H-imidazole-5-yl)pyrimidine-2-amine(26;ZH-142) 20% by wt Pd(OH)2 / C (6.50 mg) was added to a solution of methyl carbamate (47.0 mg, 0.117 mmol) in 5:3 THF / MeOH (8 mL). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through a short Celite pad, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to give a colorless solid (31.4 mg, 72%). 1 H-NMR (500MHz; CD3OD): δ 3.9(3H,s),6.41(1H,d,J=5.2Hz),7.10-7.06(2H,m),7.45-7.43(2H,m),7.79(1H,s),8.10(1H,d,J=5.2Hz); 13 C-NMR (126MHz; CD3OD): δ 34.4,112.1,116.2,116.4,127.3,128.6,128.8,129.0,131.4(d,J C-F =8.2Hz),131.6(d,JC-F =3.4Hz),141.4,142.6,159.2,159.9,163.9(d,J C-F =247Hz),164.8.HRMS(ESI + ) Calculated value C 14 H 13 FN5(M+H) 270.1155. Measured value: 270.1149.

[0247] Benzyl-(4-((ethylimino)methyl)pyrimidine-2-yl)carbamate(27) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.148 g, 0.574 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.095 g, 0.688 mmol) were added, followed by ethylamine THF solution (575 μL, 1.15 mmol, 2.0 M). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0248] Benzyl(4-(1-(ethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(28) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.199 g, 0.689 mmol), imine (0.163 g, 0.574 mmol), and a 20% K2CO3 aqueous solution (0.475 mL, 0.689 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 20 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) yielded ethyl carbamate as a grayish-white solid (79.4 mg, 33%) at mp164–171°C. 1H-NMR (500MHz; CDCl3):δ 1.28(3H,t,J=7.2Hz,4.62(2H,q,J=7.2Hz),5.23(2H,s),6.62(1H,d,J=5.4Hz),7.04 (2H,t,J=8.8Hz),7.45-7.29(7H,m),7.64(1H,s),8.12(1H,d,J=5.4Hz),9.87(1H,s); 13 C-NMR (101MHz; CDCl3): δ 16.9,42.3,67.6,115.2,115.5,115.8,124.1,128.7,128.4,128.8,130.6(d,J C-F =8.0Hz),130.8(d,J C-F =3.2Hz),135.6,139.9,144.7,151.6,157.6,157.7,159.0,162.7(d,J C-F =248Hz).HRMS(ESI + ) Calculated value C 23 H 21 FN5O2(M+H) 418.1679. Measured value: 418.1678.

[0249] 4-(1-(ethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(29;ZH-6) 20% by wt Pd(OH)2 / C (37.0 mg) was added to a 10:1 THF / MeOH (5 mL) solution of ethyl carbamate (79.0 mg, 0.189 mmol). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to give a colorless solid (54.0 mg, 84%) at mp204–212°C. 1 H-NMR(500MHz;CD3OD):δ 1.32(3H,t,J=7.2Hz),4.38(2H,q,J=7.2Hz),4.86(3H,s),6.40(1H,d,J=5.2H z),7.10-7.06(2H,m),7.45-7.42(2H,m),7.87(1H,s),8.11(1H,d,J=5.2Hz); 13C-NMR(126MHz;CD3OD):δ 16.9,42.8,112.2,116.2,116.4,126.5,131.4(d,J C-F =8.3Hz),131.7(d,J C-F =3.2Hz),140.2,142.7(s,1C),159.3,160.1,163.9(d,J C-F =247Hz),164.9.HRMS(ESI + ) Calculated value C 15 H 15 FN5(M+H) 284.1311. Measured value 284.1307.

[0250] Benzyl-(4-((tert-butylimino)methyl)pyrimidine-2-yl)carbamate(30) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.120 g, 0.465 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.071 g, 0.511 mmol) were added, followed by ethylamine THF solution (73.0 μL, 0.968 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0251] Benzyl(4-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(31) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.161 g, 0.558 mmol), imine (0.145 g, 0.465 mmol), and a 20% K2CO3 aqueous solution (0.385 mL, 0.558 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 60 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) yielded tert-butylcarbamate as a colorless solid (64.1 mg, 31%). 1 H-NMR (400MHz; CDCl3):δ 1.61(9H,s),5.27(2H,s),6.76(1H,d,J=5.0Hz),6.92(2H,t,J=8.7Hz),7.44-7.22(7H,m),7.78(1H,s),8.45(1H,d,J=5.0Hz),8.52(1H,s); 13 C-NMR (101MHz; CDCl3): δ 31.2,58.4,67.7,115.2,115.4,119.5,125.3,128.7,128.8,128.8,129.8(d,J C-F =8.2Hz),130.2(d,J C-F =3.4Hz),135.6,136.3,142.3,151.4,157.7(s,1C),159.0,162.2(d,J C-F =248Hz), 162.8.

[0252] 4-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(32;ZH9-190) 20% by wt Pd(OH)2 / C (33.0 mg) was added to a solution of tert-butylcarbamate (64.0 mg, 0.143 mmol) in 10:1 THF / MeOH (5 mL). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to give a colorless solid (30.8 mg, 69%) at mp189–197°C. 1H-NMR (500MHz; CD3OD): δ 1.61(9H,s),6.52(1H,d,J=5.0Hz),7.00-6.97(2H,m),7.32-7.29(2H,m),7.93(1H,s),8.21(1H,d,J=5.0Hz); 13 C-NMR (126MHz; CD3OD): δ 31.3,59.8,115.3,115.9,116.1,127.8,130.6(d,J C-F =8.1Hz),131.5(d,J C-F =3.4Hz),137.1,141.5,160.1,163.3,163.5(d,J C-F =246Hz),164.9.HRMS(ESI + ) Calculated value C 17 H 19 FN5(M+H) 312.1624. Measured value: 312.1619.

[0253] Benzyl-(4-((cyclopropylimino)methyl)pyrimidine-2-yl)carbamate(33) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.140 g, 0.544 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.090 g, 0.653 mmol) were added, followed by cyclopropylamine (75.0 μL, 1.09 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0254] Benzyl(4-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(34) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.189 g, 0.653 mmol), imine (0.161 g, 0.544 mmol), and a 20% K2CO3 aqueous solution (0.450 mL, 0.653 mmol) in CH2Cl2 (10 ml) was stirred at 30°C for 48 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried with (MgSO4), filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) yielded cyclopropyl carbamate as a colorless solid (50.7 mg, 22%) at mp178–188°C. 1 H-NMR (500MHz; CDCl3):δ 0.95-0.76(4H,m),4.05(1H,dt,J=7.4,3.6Hz),5.23(2H,s),6.73(1H,d,J=5.3Hz),7.0 2(2H,t,J=8.8Hz),7.46-7.31(7H,m),7.66(1H,s),8.27(1H,d,J=5.3Hz),9.12(1H,s); 13 C-NMR (126MHz; CDCl3): δ 7.4,29.4,67.6,115.6,115.7,126.6,128.7,128.8,130.3(d,J C-F =8.1Hz),130.4(d,J C-F =3.2Hz),135.7,139.7,143.4,151.5,157.5,158.0,159.0,162.6(d,J=247Hz).HRMS(ESI + ) Calculated value C 24 H 21 FN5O2(M+H) 430.1679. Measured value: 430.1676.

[0255] 4-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(35;ZH-58) 20% by weight Pd(OH)2 / C (25.0 mg) was added to a 5:2 THF / MeOH (7 mL) solution of cyclopropyl carbamate (50.7 mg, 0.118 mmol). The resulting mixture was stirred for 2.5 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to yield a colorless solid (31.9 mg, 99%). 1 H-NMR (500MHz; CDCl3):δ 0.95-0.82(4H,m),3.63(1H,tt,J=7.3,3.8Hz),5.21(2H,s),6.56(1H,d,J=5.1 Hz),7.01-6.97(2H,m),7.49-7.46(2H,m),7.63(1H,s),8.21(1H,d,J=5.1Hz); 13 C-NMR (126MHz; CDCl3): δ 7.2,28.5,112.4,115.3,115.5,127.1,129.8(d,J C-F =8.1Hz),130.4(d,J C-F =3.2Hz),138.9,141.7,158.5,159.1,162.5(d,J C-F =247Hz), 163.19.HRMS(ESI + ) Calculated value C 16 H 15 FN5(M+H) 296.1311. Measured value: 296.1306.

[0256] Benzyl-(4-((cyclobutylimino)methyl)pyrimidine-2-yl)carbamate(36) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.146 g, 0.570 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.095 g, 0.684 mmol) were added, followed by cyclobutylamine (97.0 μL, 1.14 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 11H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0257] Benzyl(4-(1-cyclobutyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(37) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.197 g, 0.684 mmol), imine (0.177 g, 0.570 mmol), and 20% K2CO3 aqueous solution (0.450 mL, 0.684 mmol) in CH2Cl2 (10 ml) was stirred at 30°C for 18 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 2:3) yielded cyclobutylcarbamate as a colorless solid (98.5 mg, 39%) at mp191–204°C. 1 H-NMR (500MHz; CDCl3):δ 1.87-1.82(2H,m),2.28-2.23(2H,m),2.45-2.40(2H,m),5.27(2H,s),5.56-5.52(1H,m),6.68(1H, d,J=5.3Hz),7.04-7.01(2H,m),7.44-7.32(7H,m),7.81(1H,s),8.23(1H,d,J=5.3Hz),9.01(1H,s); 13 C-NMR (126MHz; CDCl3): δ 15.2,31.1,50.9,67.6,115.6,115.7,116.0,124.3,128.7,128.8,130.4(d,J C-F =8.1Hz),130.7(d,J C-F =3.2Hz),135.7,137.4,144.1,151.5,157.5,157.9,159.1,162.7(d,J C-F =247.3Hz).HRMS(ESI + ) Calculated value C 25 H 23 FN5O2(M+H) 444.1836. Measured value: 444.1834.

[0258] 4-(1-cyclobutyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(38;ZH-62) 20% by wt Pd(OH)2 / C (56.0 mg) was added to a 5:2 THF / MeOH (7 mL) solution of cyclobutylcarbamate (96.0 mg, 0.216 mmol). The resulting mixture was stirred for 3 hours under a hydrogen atmosphere of 100 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to yield a colorless solid (34.2 mg, 51%) at mp229–231°C. 1 H-NMR(500MHz;CD3OD):δ 1.91-1.83(2H,m),2.45-2.35(4H,m),5.09(1H,quintet,J=8.4Hz),6.41(1H,d,J= 5.2Hz),7.09-7.05(2H,m),7.44-7.41(2H,m),8.04(1H,s),8.13(1H,d,J=5.1Hz); 13 C-NMR(126MHz;CD3OD):δ 15.8,31.8,52.1,112.6,116.2,116.4,126.7,131.2(d,J C-F =8.2Hz),131.5(d,J C-F =3.2Hz),137.9,142.1,159.4,160.1,163.9(d,J C-F =247Hz),164.9.HRMS(ESI + ) Calculated value C 17 H 17 FN5(M+H) 310.1468. Measured value: 310.1464.

[0259] Benzyl-(4-((oxetane-3-ylimino)methyl)pyrimidine-2-yl)carbamate(39) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.140 g, 0.544 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.090 g, 0.653 mmol) were added, followed by 3-oxetanamine (77.0 μL, 1.09 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0260] Benzyl(4-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(40) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.188 g, 0.653 mmol), imine (0.170 g, 0.544 mmol), and 20% K2CO3 aqueous solution (0.450 mL, 0.653 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) yielded oxetane-3-ylcarbamate as a colorless solid (113 mg, 47%) at mp186–196°C. 1 H-NMR (500MHz; CDCl3):δ 4.85(2H,t,J=6.5Hz),5.13(2H,t,J=7.2Hz),5.28(2H,s),6.31(1H,t,J=6.7Hz),6.72(1H,d,J=5. 3Hz),7.07(2H,t,J=8.6Hz,),7.46-7.34(7H,m),8.09(1H,s),8.21(1H,d,J=5.3Hz),8.70(1H,s); 13 C-NMR (126MHz; CDCl3): δ 51.4,67.8,77.9,115.5,115.8,116.0,124.5,128.8,128.9,130.4(d,J C-F =3.3Hz),130.7(d,JC-F =8.2Hz),135.6,137.4,144.8,151.4,157.4,158.2,158.2,163.0(d,J C-F =248Hz).HRMS(ESI + ) Calculated value C 24 H 21 FN5O3(M+H) 446.1628. Measured value: 446.1626.

[0261] 4-(4-(4-fluorophenyl)-1-(oxetan-3-yl)-1H-imidazole-5-yl)pyrimidine-2-amine(41;ZH-78) 20% by weight Pd(OH)2 / C (65.0 mg) was added to a 1:1 THF / MeOH (10 mL) solution of oxetane-3-ylcarbamate (102 mg, 0.229 mmol). The resulting mixture was stirred for 4 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to yield a pale yellow solid (62.7 mg, 88%). 1 H-NMR(500MHz;CD3OD):δ 4.93(2H,t,J=6.7Hz),5.05(2H,t,J=7.3Hz),5.73(1H,m,J=6.8Hz),6.37-6.36( 1H,m),7.12-7.08(2H,m),7.46-7.43(2H,m),8.06(1H,d,J=5.2Hz),8.27(1H,s); 13 C-NMR(126MHz;CD3OD):δ 53.0,54.8,78.2,111.7,116.3,116.5,126.9,131.4(d,J C-F =3.3Hz),131.6(d,J C-F =8.3Hz),138.2,143.2,159.2,159.3,164.1(d,J C-F =247Hz), 164.7.HRMS(ESI + ) Calculated value C 16 H 15 FN5O3(M+H) 312.1261. Measured value: 312.1256.

[0262] Benzyl-(4-((cyclohexylmethylimino)methyl)pyrimidine-2-yl)carbamate(42) A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.108 g, 0.419 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.069 g, 0.502 mmol) were added, followed by cyclohexylmethylamine (110 μL, 0.838 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0263] Benzyl(4-(1-(cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(43) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.145 g, 0.503 mmol), imine (0.153 g, 0.419 mmol), and 20% K2CO3 aqueous solution (0.350 mL, 0.503 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:7) yielded cyclohexylmethyl carbamate as a colorless solid (102 mg, 50%) at mp174–181°C. 1 H-NMR (500MHz; CDCl3):δ 1.64-0.83(11H,m),4.46(2H,d,J=7.2Hz),5.25(2H,s),6.65(1H,d,J=5.3Hz),7.04( 2H,t,J=8.7Hz),7.45-7.30(7H,m),7.56(1H,s),8.17(1H,d,J=5.4Hz),9.57(1H,s); 13C-NMR (126MHz; CDCl3): δ 25.7,26.3,30.4,38.9,52.9,67.6,115.6,115.7,124.3,128.7,128.8,128.8,130.6(d,J C-F =8.1Hz),130.7(d,J C-F =3.3Hz),135.6,141.2,144.5,151.5,157.6,157.8,159.4,162.6(d,J=247Hz).HRMS(ESI + ) Calculated value C 28 H 29 FN5O2(M+H) 486.2305. Measured value 486.2303.

[0264] 4-(1-(cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine (44;ZH-138) 20% by wt Pd(OH)2 / C (21.0 mg) was added to a 5:2 THF / MeOH (7 mL) solution of cyclohexyl methyl carbamate (102 mg, 0.229 mmol). The resulting mixture was stirred for 2 hours under a hydrogen atmosphere of 200 psi. The mixture was filtered through Celite, concentrated, and purified by flash chromatography (siRNA / petroleum ether 9:1) to give a colorless solid (25.1 mg, 34%) at mp180–199°C. 1 H-NMR (500MHz; CDCl3):δ 0.88-0.85(2H,m),1.14-1.11(2H,m),1.68-1.53(7H,m),4.09(2H,d,J=6.7Hz),5.18(2H,s),6.5 0(1H,d,J=5.2Hz),7.00(2H,t,J=8.8Hz),7.48-7.45(2H,m),7.54(1H,s),8.15(1H,d,J=5.2Hz); 13 C-NMR (126MHz; CDCl3): δ 25.7,26.3,30.7,39.0,52.9,112.5,115.4,115.5,125.0,130.1(d,J C-F =8.1Hz),130.7(d,J C-F =3.2Hz),140.0,142.5,158.4,159.3,162.5(d,JC-F =247Hz),163.1.HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 352.1937. Measured value: 352.1932.

[0265] [C9]

[0266] p-toluenesulfinic acid H2O (10 ml) was added to p-toluenesulfinate sodium salt (2.00 g, 10.3 mmol), and the resulting mixture was stirred for 30 minutes until a clear solution was obtained. Diethyl ether (10 ml) was added, followed by concentrated HCl (0.7 ml), and stirring was continued for another 30 minutes. The organic layer was separated, diluted with toluene (10 ml), and concentrated in a rotary evaporator until approximately 90% of the solvent was removed. Heptane (5 ml) was added, the resulting white solid was filtered, washed with heptane, and dried under vacuum to give p-toluenesulfinic acid as a white solid (1.1 g, 69%). 1 H NMR(DMSO-d6,400MHz)δ 2.37(3H,s),7.36(1H,d,J=8Hz),7.54(1H,d,J=8Hz); 13 C NMR(DMSO-d6,100MHz)δ 20.9,124.5,129.4,141.3,146.0.

[0267] N-(p-tolyl(tosyl)methyl)formamide (45) Formamide (0.937 g, 20.8 mmol) was added to a solution of p-tolualdehyde (1.00 g, 8.32 mmol) in toluene (2 ml) and acetonitrile (2 ml), followed by the addition of TMSCl (0.995 g, 9.15 mmol) and TolSO2H (1.95 g, 12.5 mmol). The resulting suspension was heated at 50°C for 5 hours. The reaction mixture was cooled to 0°C, diethyl ether (5 ml) and H2O (10 ml) were added, and the mixture was stored in a refrigerator overnight. The resulting solid white product was collected by filtration and dried under vacuum to yield compound 45 (0.810 g, 33%). Compound 45 exists as a 5:1 mixture of amide rotational isomers in DMSO-d6 at room temperature. Spectral data of the main isomers: 1 H NMR(DMSO-d6,400MHz)δ 2.31(3H,s),2.39(3H,s),6.31(1H,d,J=10.4Hz),7.21(2H,d,J=7.6Hz),7. 40-7.42(4H,m),7.69(2H,d,J=8.0Hz),7.93(1H,s),9.70(1H,d,J=10.4Hz); 13 C NMR(DMSO-d6,100MHz)δ 21.3,21.6,70.4,127.7,129.3,129.7,129.8,130.0,134.0,139.5,145.2,160.6.

[0268] 1-(isocyano(p-tolyl)methyl)sulfonyl)-4-methylbenzene(46) 0.493 ml of phosphorus oxychloride (0.527 mmol) was added to 25 (0.80 g, 0.263 mmol) of dry THF (5 ml) solution, and the resulting solution was stirred at 25°C for 5 minutes. After cooling the solution to 0°C, triethylamine (2.21 ml, 1.58 mmol) was slowly added. The reaction mixture was warmed to 5–10°C and maintained at that temperature for 45 minutes. Ethyl acetate (5 ml) and water (5 ml) were added sequentially, and the mixture was stirred for 5 minutes. The organic layer was separated, washed with water, saturated NaHCO3, and brine, and evaporated to dryness. The residue was diluted with 1-propanol (5 ml), and this solution was concentrated to approximately half of its original volume (2.5 ml) using a rotary evaporator. The residue was cooled to 5–10°C for 30 minutes, the crystallized light brown solid was filtered, rinsed twice with 1-propanol, and dried under vacuum to yield 46 (0.420 g, 56%). 1 H NMR(CDCl3,400MHz)δ 2.39(3H,s),2.47(3H,s),5.57(1H,s),7.18-7.24(4H,m),7.33(2H,d,J=8.4Hz),7.63(2H,d,J=8Hz); 13 C NMR(CDCl3,100MHz)δ 21.3,21.8,76.4,123.5,128.3,129.5,129.7,130.2,130.5,141.1,146.5,165.8.

[0269] Benzyl(4-(1-(cyclohexyl)-4-(4-methylphenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(47) 1-(isocyano(p-tolyl)methyl)sulfonyl)-4-methylbenzene 46 (0.250 g, 0.876 mmol) and a 20% K2CO3 aqueous solution (1.2 mL, containing 0.242 g, 1.75 mmol) were added to a solution of imine 12 (0.267 g, 0.788 mmol) in CH2Cl2 (5 ml) at 20°C, while stirring was continued overnight. At this point, additional imine (0.029 g, 0.088 mmol) and K2CO3 (0.061 g, 0.086 mmol) were added, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 6:93:1) followed by recrystallization with methanol gave 47 as a white solid (0.062 g, 15%). 1 H NMR(CDCl3,400MHz)δ 1.21-1.28(2H,m),1.37-1.47(2H,m),1.58-1.74(2H,m),1.82-1.85(2H,m),2.10-2.13(2H,m),2.35(3H,s),4.99-5.02(1H,m) ,5.27(2H,s),6.85(1H,d,J=5.2Hz),7.12(1H,d,J=8.4Hz),7.32-7.46(7H,m),7.60(1H,s),7.77(1H,s),8.35(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 21.4,25.7,34.7,55.4,67.6,116.9,123.9,128.6,128.7,128.8,129.3, 131.7,135.6,136.8,137.7,144.9,151.3,157.4,158.0,159.8;HRMS(ESI + ) Calculated value C 28 H 30 N5O2(M+H) 468.2400. Measured value 468.2402.

[0270] 4-(1-(1-(cyclohexyl)-4-(4-methylphenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(48;SS8-186) A mixture of 47 (0.050 g, 0.012 mmol) and 20 wt% Pd(OH)2 / C (0.010 g) in THF (3 ml) and methanol (0.3 ml) was treated with hydrogen at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 7:92:1) gave 48 as a white solid (0.020 g, 50%). 1 H NMR(CDCl3,400MHz)δ 1.26-1.40(4H,m),1.56-1.75(2H,m),1.86-1.90(2H,m),2.15-2.17(2H,m),2.35(3H,s),4.49-4.57(1H,m),5.0 9(2H,s),6.54(1H,d,J=5.2Hz),7.10(2H,d,J=8.0Hz),7.37(2H,d,J=8.0Hz),7.73(1H,s),8.15(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 21.4,25.5,26.0,55.7,113.2,124.6,128.3,129.2,131.7,135.9,137.2,143.0,158.4,159.8,163.1;HRMS(ESI + ) Calculated value C 20 H 24 N5(M+H) 334.2032. Measured value 334.2028.

[0271] [C10]

[0272] N-((4-chlorophenyl)(tosyl)methyl)formamide(49) Formamide (0.801 g, 17.8 mmol) was added to a solution of p-tolualdehyde (1.00 g, 7.11 mmol) in toluene (2 ml) and acetonitrile (2 ml), followed by the addition of TMSCl (0.850 g, 7.83 mmol) and TolSO2H (1.66 g, 10.7 mmol). The resulting suspension was heated at 50°C for 5 hours. The reaction mixture was cooled to 0°C, diethyl ether (5 ml) and H2O (10 ml) were added, and the mixture was stored overnight in a refrigerator. The resulting solid white product was collected by filtration and dried under high vacuum to give compound 49 (0.90 g, 39%). Compound 49 exists as a 3:1 mixture of amide rotational isomers in DMSO-d6 at room temperature. The spectra of the major isomers are as follows: 1 H NMR(DMSO-d6,400MHz)δ 2.39(3H,s),6.43(1H,d,J=10.4Hz),7.41-7.51(4H,m),7.57(2H,d,J=8.4Hz),7.70(2H,d,J=8.0Hz),7.94(1H,s),9.77(1H,d,J=10.8Hz); 13 C NMR(DMSO-d6,100MHz)δ 21.6,69.9,124.9,128.7,129.6,130.1,131.7,133.6,134.9,145.5,160.7.

[0273] 1-(chloro-4-isocyano(tolyl)methyl)benzene(50) 0.462 ml of phosphorus oxychloride (0.494 mmol) was added to 49 (0.800 g, 0.247 mmol) of dry THF (5 ml) solution, and the resulting solution was stirred at 25°C for 5 minutes. After cooling the solution to 0°C, triethylamine (2.06 ml, 1.48 mmol) was slowly added. The reaction mixture was warmed to 5–10°C and maintained at that temperature for 45 minutes. Ethyl acetate (5 ml) and water (5 ml) were added sequentially, and the mixture was stirred for 5 minutes. The organic layer was separated, washed with water, saturated NaHCO3, and brine, and evaporated to dryness. The resulting residue was diluted with 1-propanol (5 ml), and the resulting solution was concentrated to half its original volume (2.5 ml) using a rotary evaporator. The residue was cooled to 5-10°C for 30 minutes, the crystallized light brown solid was filtered, rinsed twice with 1-propanol, and dried under high vacuum to yield 50 (0.115 g, 14%). 1 H NMR(CDCl3,400MHz)δ 2.48(3H,s),5.58(1H,s),7.28(2H,d,J=8.4Hz),7.34-7.49(4H,m),7.63(2H,d,J=8.0Hz); 13 C NMR(CDCl3,100MHz)δ 21.8,75.8,125.1,129.1,129.7,129.8,129.9,130.5,137.2,146.9,166.6.

[0274] Benzyl(4-(1-(cyclohexyl)-4-(4-chlorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate(51) 1-(chloro-4-isocyano(tolyl)methyl)benzene 50 (0.120 g, 0.392 mmol) and 20% K2CO3 aqueous solution (0.108 g, 0.785 mmol) were added to a solution of imine 12 (0.119 g, 0.353 mmol) in CH2Cl2 (5 ml) at 20°C, while stirring was continued overnight. At this point, additional imine (0.013 g, 0.062 mmol) and K2CO3 (0.047 g, 0.345 mmol) were added, and the reaction mixture was stirred overnight at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried in (MgSO4), filtered, and concentrated. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 6:93:1) followed by recrystallization using CH3OH / CH2Cl2 yielded 51 as a white solid (0.051 g, 20%). 1 H NMR(CDCl3,400MHz)δ 1.21-1.28(2H,m),1.36-1.46(2H,m),1.56-1.74(2H,m),1.82-1.86(2H,m),2.10-2.13(2H,m),4.96-5.02(1H,m),5.27( 2H,s),6.81(1H,d,J=5.6Hz),7.29(1H,d,J=8.8Hz),7.32-7.46(7H,m),7.69(1H,s),7.78(1H,s),8.38(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ HRMS(ESI + ) Calculated value C 27 H 27 35 ClN5O2(M+H) 488.1853. Measured value 488.1861.

[0275] 4-(1-(1-(cyclohexyl)-4-(4-chlorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine(52;SS8-190) A mixture of 50 (0.050 g, 0.102 mmol) and 20 wt% Pd(OH)2 / C (0.020 g) in THF (5 ml) and methanol (0.5 ml) was treated with hydrogen at 200 psi for 1 hour. The mixture was filtered through Celite and concentrated under reduced pressure to give the crude product. Flash chromatography of the residue (MeOH / CHCl3 / Et3N 20:79:1) gave 52 contaminated with the dechlorinated compound. 1 H NMR(CDCl3,400MHz)δ 1.23-1.42(4H,m),1.56-1.76(2H,m),1.87-1.91(2H,m),2.15-2.17(2H,m),4.49-4.55(1H,m),5.06(2H,s), 6.54(1H,d,J=5.2Hz),7.26-7.30(2H,m),7.49(2H,d,J=8.0Hz),7.75(1H,s),8.16(1H,d,J=5.2Hz);HRMS(ESI + ) Calculated value C 19 H 20 35 ClN5(M+H) 354.1485. Measured value 354.1479.

[0276] [C11]

[0277] 2-(methylamino)pyrimidine-4-carbaldehyde hydrochloride (53) A 4M aqueous solution (2 ml) of 4-(dimethoxymethyl)-N-methylpyrimidine-2-amine (0.060 g, 0.33 mmol) was added to a THF (1 ml) solution. The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0278] 4-((cyclohexylimino)-methyl)-N-methylpyrimidine-2-amine(54) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 53 (0.045 g, 0.33 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol) while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.55 g, 0.39 mmol) were added, followed by cyclohexylamine (0.38 g, 0.39 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 1 ¹H NMR analysis showed complete consumption of the aldehyde. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried, filtered, and concentrated. The crude material was used in the next step without purification (0.068 g, 48%). 1 H NMR(CDCl3,400MHz)δ 1.25-1.43(2H,m),1.53-1.67(8H,m),5.10-5.14(1H,m),7.12(1H,d,J=4.8Hz),8.12(1H,s,NH),8.34(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 24.6,25.6,34.0,69.8,112.4,151.6,157.8,158.9,163.2;HRMS(ESI + ) Calculated value C 12 H 19 N4(M+H)219.1610. Measured value 219.1622.

[0279] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-N-methylpyrimidine-2-amine(55;SS9-010) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.060 g, 0.275 mmol), imine 54 (0.088 g, 0.306 mmol), and 20% K2CO3 aqueous solution (0.085 g, 0.612 mmol) in CH2Cl2 (5 ml) at 20°C was stirred overnight. At this point, additional imine (5.0 mg, 0.027 mmol) and K2CO3 (7.0 mg, 0.056 mmol) were added, and the reaction mixture was stirred for a second night at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Â / petroleum ether 6:4) yielded 55 as a white solid (0.045 g, 48%). 1 H NMR(CDCl3,400MHz)δ 1.20-1.40(4H,m),1.61-1.76(2H,m),1.88-1.91(2H,m),2.18-2.21(2H,m),2.10-2.13(2H,m),3.06(3H,d,J=11.6Hz),4.57-4.65(1H,br s),5.13-5.15(1H,m),6.41(1H,d,J=5.2Hz),6.96-7.01(2H,m),7.44-7.49(2H,m),7.73(1H,s),8.16(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 25.5,26.1,28.6,34.7,55.7,111.9,115.2,115.5,130.1,130.2,135.9,158.3,159.0,159.5,163.2,163.6;HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 352.1937. Measured value: 352.1935.

[0280] [C12]

[0281] Pyrrolidine-1-carboxyimidoamide sulfate (56) Equimolar amounts of pyrrolidine (1.77 ml, 21.5 mmol) and 2-methyl-2-thiopseudourea sulfate (3.00 g, 21.5 mmol) in water (10 ml) were heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, and concentrated H2SO4 (2.25 ml, 21.5 mmol) was added. The solvent was evaporated, the resulting solid was filtered, washed with acetone, and dried to give 56 as a white solid (3.10 g, 86%). 1 H NMR(D2O,400MHz)δ 1.98-2.01(4H,m),3.38-3.40(4H,m); 13 C NMR(D2O,100MHz)δ 24.8,46.8,154.1;HRMS(ESI + ) Calculated value C5H 12 N3(M+H) 114.1031. Measured value 114.2028.

[0282] 1,1-Dimethylguanidine sulfate (57) Dimethylamine (40% w / v H2O) (3.08 ml, 28.7 mmol) and 2-methyl-2-thiopseudourea sulfate (2.00 g, 14.3 mmol) in water (10 ml) were stirred at room temperature for 3 days. The reaction mixture was allowed to cool to room temperature, and concentrated H2SO4 (0.76 ml, 14.3 mmol) was added. The solvent was evaporated, the resulting solid was filtered, washed with acetone, and dried to give 57 as a white solid (2.01 g, 98%) at 280°C. 1 H NMR(D2O,400MHz)δ 3.03(6H,s); 13 C NMR(D2O,100MHz)δ 37.3,156.7;HRMS(ESI + ) Calculated value C3H 10 N3(M+H)88.0875. Measured value: 88.0878.

[0283] 1-Benzylguanidine sulfate (58) Benzylamine (1.57 ml, 17.2 mmol) was added to a solution of 2-methyl-2-thiopseudourea sulfate (2.00 g, 14.3 mmol) in water (10 ml) and ethanol (10 ml). The resulting reaction mixture was heated under reflux for 12 hours. The reaction mixture was allowed to cool to room temperature, and concentrated H2SO4 (0.76 ml, 14.3 mmol) was added. The solvent was evaporated, the resulting solid was filtered, washed with diethyl ether, and dried to give 58 as a white solid (2.36 g, 72%). 1 H NMR(D2O,400MHz)δ 3.82(2H,s),7.23-7.27(5H,m); 13 C NMR(D2O,100MHz)δ 44.4,126.8,127.9,128.9,136.1,156.8;HRMS(ESI + ) Calculated value C8H 12 N3(M+H) 150.1031. Measured value 150.1037.

[0284] 1-Propylguanidine sulfate (59) Propylamine (1.77 ml, 22.1 mmol) and 2-methyl-2-thiopseudourea sulfate (2.00 g, 14.3 mmol) in water (10 ml) were stirred at room temperature for 3 days. The reaction mixture was allowed to cool to room temperature, and concentrated H2SO4 (0.76 ml, 14.3 mmol) was added. The solvent was evaporated, the resulting solid was filtered, washed with diethyl ether, and dried to give 59 as a white solid (2.22 g, 99%). 1 H NMR(D2O,400MHz)δ 0.92(3H,t,J=8Hz),1.56-1.61(2H,sex,J=8Hz),3.12(3H,t,J=8Hz); 13 C NMR(D2O,100MHz)δ 10.3,21.3,42.7,156.7;HRMS(ESI + ) Calculated value C4H 12 N3(M+H) 102.1031. Measured value 102.1037.

[0285] 4-(dimethoxymethyl)-2-(pyrrolidine-1-yl)pyrimidine (60) Sodium hydroxide (0.706 g, 17.6 mmol) and 56 (1.00 g, 8.83 mmol) were added to a solution of E-1,1-dimethoxy-4-dimethylaminobuta-2-en-2-one (2.29 g, 13.2 mmol) in 10 ml of water. The resulting mixture was heated under reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature and filtered to remove precipitated sodium sulfate. The aqueous filtrate was extracted several times with CH2Cl2. The combined organic layers were dried over (MgSO4), filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 1:1) yielded 60 as a pale yellow oil (0.110 g, 10%). 1 H NMR(CDCl3,400MHz)δ 1.96-2.00(4H,m),3.42(6H,m),3.57-3.60(4H,m),5.08(1H,s),6.68(1H,d,J=5.2Hz),8.34(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 25.7,46.8,54.0,103.8,105.7,158.4,160.3,165.9;HRMS(ESI + ) Calculated value C 11 H 18 N3O2(M+H) 224.1399. Measured value 224.1398

[0286] 4-(dimethoxymethyl)-N,N-dimethylpyrimidine-2-amine(61) Sodium hydroxide (0.867 g, 7.35 mmol) and 57 (1.00 g, 7.35 mmol) were added to a solution of E-1,1-dimethoxy-4-dimethylaminobuta-2-en-2-one (1.91 g, 11.0 mmol) in 10 ml of water. The resulting mixture was heated under reflux for 16 hours. The reaction product was diluted with CH2Cl2 and washed with water. After several extractions, the combined organic layer was dried over (MgSO4), filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 1:1) yielded 61 as a pale yellow oil (0.09 g, 7%). 1H NMR(CDCl3,400MHz)δ 3.18(6H,s),3.41(6H,s),5.08(1H,s),6.66(1H,d,J=5.2Hz),8.33(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 37.1,54.0,103.9,105.7,158.4,162.3,165.6;HRMS(ESI + ) Calculated value C9H 16 N3O2(M+H) 198.1243. Measured value 198.1238.

[0287] N-benzyl-4-(dimethoxymethyl)pyrimidine-2-amine(62) Sodium hydroxide (0.606 g, 15.2 mmol) and 58 (1.50 g, 7.57 mmol) were added to a solution of E-1,1-dimethoxy-4-dimethylaminobuta-2-en-2-one (1.97 g, 11.3 mmol) in 10 ml of water. The resulting mixture was heated under reflux for 16 hours. The reaction product was diluted with CH2Cl2 and washed with water. After several extractions, the combined organic layers were dried (MgSO4), filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 1:1) yielded 62 as a pale yellow oil (0.6 g, 31%). 1 H NMR(CDCl3,400MHz)δ 3.39(6H,s),5.65(2H,d,J=6Hz),5.10(1H,s),5.57(1H,br s),6.77(1H,d,J=5.2Hz),7.24-7.36(5H,m),8.33(1H,d,J=4.8Hz); 13 C NMR(CDCl3,100MHz)δ 45.7,53.8,103.0,108.0,127.4,127.7,128.7,139.2,159.0,162.4,166.2;HRMS(ESI + ) Calculated value C 14 H 17 N3O2(M+H) 260.1399. Measured value 260.1401.

[0288] 4-(dimethoxymethyl)-N-propylpyrimidine-2-amine(63) Sodium hydroxide (0.80 g, 20.1 mmol) and 59 (1.50 g, 10.1 mmol) were added to a solution of E-1,1-dimethoxy-4-dimethylaminobuta-2-en-2-one (2.07 g, 12.1 mmol) in 10 ml of water. The resulting mixture was heated under reflux for 16 hours. The reaction product was diluted with CH2Cl2 and washed with water. After several extractions, the combined organic layers were dried (MgSO4), filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 1:1) yielded 63 as a pale yellow oil (0.25 g, 12%). 1 H NMR(CDCl3,400MHz)δ 0.97(3H,t,J=8Hz),1.59-1.65(2H,m),3.36-3.41(2H,m),3.39(6H,s),5.09(1H,s),6.72(1H,d,J=4.8Hz),8.33(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 11.6,22.9,43.5,53.7,103.0,107.5,158.9,162.6,166.1;HRMS(ESI + ) Calculated value C 10 H 18 N3O2(M+H) 212.1399. Measured value 212.1401

[0289] 1-(4-formylpyrimidine-2-yl)pyrrolidine hydrochloride (64) A 4M aqueous solution (2 ml) was added to a 60 (0.080 g, 0.358 mmol) THF (1 ml) solution. The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0290] 2-(dimethylamino)pyrimidine-4-carbaldehyde hydrochloride (65) A 4M aqueous solution (2 ml) of HCl was added to a solution of 61 (0.080 g, 0.406 mmol) of THF (1 ml). The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0291] 2-(benzylamino)pyrimidine-4-carbaldehyde hydrochloride (66) A 4M aqueous solution (2 ml) of HCl was added to a solution of 62 (0.200 g, 0.772 mmol) of THF (1 ml). The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0292] 2-(Propylamino)pyrimidine-4-carbaldehyde hydrochloride (67) A 4M aqueous solution (2 ml) was added to a solution of 63 (0.200 g, 0.948 mmol) THF (1 ml). The resulting mixture was heated overnight at 40°C and then cooled to room temperature. The reaction mixture containing the aldehyde hydrochloride was used directly in the next step without isolation.

[0293] N-((2-(pyrroridine-1-yl)pyrimidine-4-yl)methylene)cyclohexaneamine(68) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 64 (0.060 g, 0.338 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol), while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.047 g, 0.338 mmol) were added, followed by cyclohexylamine (0.040 g, 0.406 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. 1 ¹H NMR analysis showed complete consumption of the aldehyde. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried, filtered, and concentrated. The crude material was used in the next step without purification (0.080 g, 91%). 1 H NMR(CDCl3,400MHz)δ 1.25-1.42(4H,m),1.66-1.84(6H,m),1.98-2.01(4H,m),3.26-3.31(1H,m),3. 58-3.61(4H,m),7.08(1H,d,J=4.8Hz),8.15(1H,s,NH),8.34(1H,d,J=5.2Hz); 13C NMR(CDCl3,100MHz)δ 24.6,25.5,25.6,34.0,46.6,69.7,104.8,158.1,158.3,159.7,162.2;HRMS(ESI + ) Calculated value C 15 H 23 N4(M+H)259.1923. Measured value 259.1915

[0294] 4-((cyclohexylimino)-methyl)-N,N-dimethylpyrimidine-2-amine(69) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 65 (0.063 g, 0.417 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol), while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.057 g, 0.417 mmol) were added, followed by cyclohexylamine (0.049 g, 0.534 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. 1 ¹H NMR analysis showed complete consumption of the aldehyde. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried, filtered, and concentrated. The crude material was used in the next step without purification (0.091 g, 93%). 1 H NMR(CDCl3,400MHz)δ 1.02-1.43(4H,m),1.61-1.85(6H,m),3.19(3H ,s),3.21(3H,s),3.24-3.31(1H,m),7.08(1H,d,J=5.2Hz),8.14(1H,s,NH),8.34(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 24.8,25.7,34.2,37.2,69.9,105.0,158.2,158.4,159.9,162.3;HRMS(ESI + ) Calculated value C 13 H 24 N4(M+H)233.1766. Measured value 233.1758

[0295] N-benzyl-4-((cyclohexylimino)-methyl)pyrimidine-2-amine(70) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 66 (0.2 g, 0.939 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol), while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.129 g, 0.939 mmol) were added, followed by cyclohexylamine (0.112 g, 11.3 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. 1 ¹H NMR analysis showed complete consumption of the aldehyde. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The crude material was used in the next step without purification (0.250 g, 92%). 1 H NMR(CDCl3,400MHz)δ 1.24-1.38(4H,m),1.56-1.68(4H,m),1.81-1.84(2H,m),3.24-3.31(1H,m),3.39(2 H,s),6.73(1H,d,J=4.8Hz),7.24-7.27(5H,m),8.11(1H,s),8.32(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 24.7,25.6,33.9,45.5,69.8,107.8,127.2,127.4,128.5,139.08,158.8,158.9,162.4,166.0;HRMS(ESI + ) Calculated value C 12 H 19 N4(M+H) 295.1923. Measured value 295.1915.

[0296] 4-((cyclohexylimino)-methyl)-N-propylpyrimidine-2-amine(71) A 45% KOH aqueous solution (0.448 g, 7.98 mmol) was added to an ice-cold solution of crude aldehyde 67 (0.15 g, 0.908 mmol) in an HCl aqueous solution (2 ml, 7.94 mmol), while maintaining the temperature below 15°C. To the neutralized mixture, CH2Cl2 (5 ml) and K2CO3 (0.125 g, 0.908 mmol) were added, followed by cyclohexylamine (0.108 g, 11.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. 1 ¹H NMR analysis showed complete consumption of the aldehyde. The reaction mixture was diluted with CH₂Cl₂, washed with water, dried (MgSO₄), filtered, and concentrated. The crude material was used in the next step without purification (0.250 g, 91%). 1 H NMR(CDCl3,400MHz)δ 0.96-1.00(3H,t,J=8Hz),1.24-1.38(4H,m),1.56-1.84(8H,m),3.25-3.30(1H,m),3.39(2H,t,J=8.4Hz),5.09(1H,br s),6.72(1H,d,J=5.2Hz),8.11(1H,s,NH),8.32(1H,d,J=4.8Hz); 13 C NMR(CDCl3,100MHz)δ 11.4,22.8,24.6,25.1,43.3,69.9,105.0,158.2,158.4,159.9,162.3;HRMS(ESI + ) Calculated value C 12 H 19 N4(M+H)247.1923. Measured value: 247.1915.

[0297] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-2-(pyrrolidine-1-yl)pyrimidine (72; SS9-098) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.099 g, 0.344 mmol), crude imine 68 (0.070 g, 0.309 mmol), and 20% K2CO3 aqueous solution (0.095 g, 0.688 mmol) in CH2Cl2 (5 ml) at 20°C was stirred overnight. At this point, additional K2CO3 (0.024 g, 0.172 mmol) was added, and the reaction mixture was stirred for a second night at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 4:6) yielded an impure product, which was re-purified by HPLC to yield 72 (0.028 g, 26%). 1 H NMR(MeOH,400MHz,HCl salt)δ 1.11-1.31(4H,m),1.39-1.69(4H,m),1.75-1.81(2H,m),1.75-1.81(2H,m),1.95-2.01(2H,m),2.09-2.16(2H,m),3.48-3.7 1(4H,m),4.75-4.81(1H,m),6.49(1H,d,J=6.4Hz),7.13-7.18(2H,m),7.36-7.40(2H,m),7.94(1H,d,J=6.8Hz),9.03(1H,s); 13 C NMR(CDCl3,100MHz)δ 24.7,25.7,34.0,47.3,58.2,109.7,116.6,116.8,122.9,130.7,130.8,155.9,157.6,162.5,165.0;HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 392.2250. Measured value: 392.2247.

[0298] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-N,N-dimethylpyrimidine-2-amine(73;SS9-078) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.124 g, 0.430 mmol), crude imine 69 (0.090 g, 0.387 mmol), and 20% K2CO3 aqueous solution (0.119 g, 0.861 mmol) in CH2Cl2 (5 ml) at 20°C was stirred overnight. At this point, additional K2CO3 (0.030 g, 0.215 mmol) was added, and the reaction mixture was stirred at 30°C for a second night. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 6:4) yielded an impure product, which was re-purified by HPLC to yield 73 (0.022 g, 14%). 1 H NMR(CDCl3,400MHz)δ 1.25-1.39(4H,m),1.73-1.79(2H,m),1.95-1.98(2H,m),2.24-2.26(2H,m),3.26(6H,s),4.70-4.75(1 H,m),6.31(1H,d,J=5.2Hz),7.09-7.12(2H,m),7.46-7.48(2H,m),8.32(1H,d,J=5.2Hz),8.85(1H,s); 13 C NMR(CDCl3,100MHz)δ HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 366.2094. Measured value 365.2089.

[0299] N-benzyl-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine (74; SS9-102) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.273 g, 0.945 mmol), crude imine 69 (0.230 g, 0.850 mmol), and 20% K2CO3 aqueous solution (0.261 g, 1.891 mmol) in 5 ml of CH2Cl2 at 20°C was stirred overnight. At this point, additional K2CO3 (0.065 g, 0.472 mmol) and imine (0.023 g, 0.085 mmol) were added, and the reaction mixture was stirred for a second night at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 6:4) yielded 74 as a white solid (0.110 g, 35%). 1 H NMR(CDCl3,400MHz)δ 1.19-1.25(4H,m),1.56-1.62(2H,m),1.81-1.86(2H,m),2.11-2.14(2H,m),4.54-4.57(1H,m),4.71(2H,d,J=6.0Hz),5.55(1H,br s),6.44(1H,d,J=5.2Hz),6.96-7.01(2H,m),7.28-7.31(1H,m),7.34-7.37(4H,m),7.44-7.47(2H,m),7.72(1H,s),8.16(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ 25.3,25.7,34.5,45.3,55.4,112.3,115.2,115.3,125.0,127.2,127.3,128.7,129 .9,130.0,130.7,135.7,140.0,141.6,158.3,160.0,161.0,62.4,163.5;HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 428.2250. Measured value: 428.2247.

[0300] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-propylpyrimidine-2-amine(75;SS9-106) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.260 g, 0.902 mmol), crude imine 71 (0.200 g, 0.812 mmol), and 20% K2CO3 aqueous solution (0.250 g, 1.812 mmol) in CH2Cl2 (5 ml) at 20°C was stirred overnight. At this point, additional K2CO3 (0.064 g, 0.448 mmol) and imine (0.021 g, 0.081 mmol) were added, and the reaction mixture was stirred for a second night at 30°C. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (siRNA / petroleum ether 6:4) yielded 75 as a white solid (0.085 g, 23%). 1 H NMR(CDCl3,400MHz)δ 1.01(3H,t,J=7.2Hz),1.23-1.39(4H,m),1.59-1.76(4H,m),1.88-1.91(2H,m),2.16-2.19(2H,m),3.43(2H,q,J=7.2Hz),4.55-4.58(1H,br s),5.19-5.35(1H,m),6.38(1H,d,J=5.2Hz),6.98-7.01(2H,m),7.43-7.47(2H,m),7.72(1H,s),8.14(1H,d,J=5.2Hz); 13 C NMR(CDCl3,100MHz)δ HRMS(ESI + ) Calculated value C 20 H 23 FN5(M+H) 380.2250. Measured value: 380.2246.

[0301] [C13]

[0302] 4-Dimethoxymethyl-2-methylsulfanylpyrimidine (76) A mixture of 1,1-dimethoxy-4-dimethylaminobuta-2-en-2-one (5.00 g, 28.9 mmol), thiourea (3.30 g, 43.4 mmol), and 2.5 M NaOMe (2.34 g, 43.4 mmol) in MeOH (80 mL) was heated under reflux overnight. The mixture was cooled to room temperature, and then MeI (2.16 mL, 34.7 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was extracted in HCl, washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (HCl / petroleum ether 1:5) to give thioether (4.14 g, 72%) as a colorless oil. 1 H NMR(CDCl3,400MHz)δ 2.91(3H,s),5.67(6H,s),5.18(1H,s),7.18(1H,d,J=4.0Hz),8.56(1H,d,J=4.0Hz); 13 C NMR(CDCl3,100MHz)δ 14.3,54.2,103.2,113.4,158.0,165.7,172.8.

[0303] 2-(methylthio)pyrimidine-4-carbaldehyde (77) A 4M aqueous solution (13 ml) was added to a solution of 4-dimethoxymethyl-2-methylsulfanylpyrimidine (4.10 g, 20.5 mmol). The resulting mixture was heated at 50°C overnight. 1 ¹H NMR analysis indicated conversion to carboaldehyde, so the mixture was cooled to room temperature. The reaction mixture was diluted with toluene and neutralized with K₂CO₃ solution. The aqueous phase was extracted with toluene, dried over MgSO₄, and concentrated. The crude material was used in the next step without purification (2.74 g, 87%). 1 H NMR(CDCl3,400MHz)δ 2.64(3H,s),7.44(1H,d,J=4.8Hz),8.77(1H,d,J=4.8Hz),9.96(1H,s).

[0304] 4-((cyclohexylimino)-methyl)-N-methylthiopyrimidine-2-amine(78) A 20% aqueous solution of K2CO3 (0.55 g, 0.39 mmol) and cyclohexylamine (2.45 mL, 21.4 mmol) were added to a solution of crude aldehyde (2.74 g, 17.8 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred overnight at room temperature. 1 1H NMR analysis showed complete consumption of the aldehyde. The reaction mixture containing the imine was used directly in the next step without isolation.

[0305] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-2-(methylthio)pyrimidine (79) A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (5.67 g, 19.6 mmol), imine (2.74 g, 17.8 mmol), and K2CO3 (2.71 g, 19.6 mmol) in CH2Cl2 (15 ml) was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (1:1 HCl / petroleum ether) yielded a solid, which was recrystallized from HCl / petroleum ether to give sulfide as pale yellow crystals (2.32 g, 35%) at 192–195°C. 1 H-NMR (400MHz; CDCl3):δ 1.41-1.19(3H,m),1.75-1.59(3H,m),1.88(2H,d,J=13.3Hz),2.16(2H,d,J=11.3Hz),2.58(3H,s),4.62(1H,tt,J=11.9 ,3.4Hz),6.76(1H,d,J=5.2Hz),6.99(2H,t,J=8.6Hz),7.40(2H,dd,J=8.5,5.5Hz),7.76(1H,s),8.31(1H,d,J=5.2Hz); 13 C-NMR (101MHz; CDCl3): δ 14.2,25.4,26.0,34.7,55.9,115.5,115.71(s,1C),117.2,124.2,130.3(d,J C-F =8.0Hz),130.6(d,J C-F =3.2Hz),136.6,143.1,157.1,158.2,162.6(d,JC-F= 247Hz), 173.0.HRMS(ESI + ) Calculated value C 20 H 22 FN4S(M+H) 369.1549. Measured value: 369.1545.

[0306] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-2-methylsulfonylpyrimidine-2-amine(80) A mixture of sulfides (0.404 g, 1.10 mmol) in CH2Cl2 (20 mL) was gradually mixed with mCPBA (0.569 g, 3.30 mmol), and the mixture was stirred overnight at room temperature. TLC showed conversion to a more polar compound. The mixture was quenched with aqueous Na2CO3 solution, water, and brine, dried over Na2SO4, and concentrated under vacuum to give the sulfone as a colorless solid (0.440 g, 87%) at 196–202°C. 1 H-NMR (400MHz; CDCl3):δ 1.93-1.21(8H,m),2.23(2H,d,J=11.3Hz),3.39(3H,s),4.85(1H,tt,J=11.8,3.4Hz),7.08(2 H,t,J=8.6Hz),7.27(1H,m),7.43(2H,dd,J=8.5,5.5Hz),7.86(1H,s),8.59(1H,d,J=5.4Hz); 13 C-NMR (101MHz; CDCl3): δ 25.5,25.8,34.9,39.2,56.9,116.0,116.3,123.1,130.3(d,J C-F =3.6Hz,1C),130.7(d,J C-F =8.2Hz),138.2,146.0,157.5,159.8,163.1(d,J C-F =249Hz),166.3.HRMS(ESI + ) Calculated value C 20 H 22 FN4O2S(M+H)401.1447. Measured value: 401.1444.

[0307] N-Cyclobutyl-4-(1-Cyclohexyl-4-(4-Fluorophenyl)-1H-Imidazole-5-yl)pyrimidine-2-amine(81) Cyclobutylamine (35.0 μL, 0.569 mmol) was added to a mixture of 80 (38.0 mg, 0.095 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 40 hours. The mixture was concentrated under vacuum, and the compound was purified by flash chromatography (Â1:1 Â1) to give a pale yellow solid (37.0 mg, 99%) at mp185–189°C. 1 H-NMR (500MHz; CDCl3): δ 1.99-1.29(13H,m,),2.17(2H,d,J=11.2Hz),2.43(2H,qd,J=7.7,3.3Hz,),4.50(1H,dq,J=16.1,8.0Hz),4.60(1H,br s),5.46(1H,br s),6.38(1H,d,J=5.1Hz),7.00-6.96(2H,m),7.46-7.44(2H,m),7.73(1H,s),8.13(1H,d,J=4.3Hz); 13 C-NMR (126MHz; CDCl3): δ 15.2,25.5,26.0,31.9,34.7,46.6,55.5,112.1,115.2,115.4,125.2,130.1(d,J C-F =8.0Hz),130.8(d,J C-F =3.1Hz),135.8,141.6,158.3,159.1,161.7,162.4(d,J C-F =247Hz).HRMS(ESI + ) Calculated value C 23 H 27 FN5(M+H) 392.2250. Measured value: 392.2247.

[0308] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-N-(oxetan-3-yl)pyrimidine-2-amine(82) 3-oxetanamine (48.0 μL, 0.053 mmol) was added to a mixture of 80 (48.0 mg, 0.120 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 24 hours. Since TLC indicated that the reaction was incomplete, an additional 3-oxetanamine (48 μL, 0.053 mmol) was added, and stirring was continued for a further 48 hours. The mixture was concentrated under vacuum, and the compound was purified by flash chromatography (RINKAN / petroleum ether 1:1) to give a pale yellow solid (44.9 mg, 95%). 1 H-NMR (500MHz; CDCl3):δ 1.92-1.27(8H,m),2.15-2.12(2H,m),4.48(1H.dd,J=9.6,6.0Hz),4.62(2H,t,J=6.5Hz),4.98(2H,t,J=7.0Hz),5.15(1H ,q,J=6.8Hz),6.46(1H,d,J=5.1Hz),6.99-6.95(2H,m),7.41(2H,td,J=6.1,2.6Hz),7.74(1H,s),8.17(1H,d,J=5.1Hz); 13 C NMR(126MHz;CDCl3)δ 21.2,25.4,26.0,34.64,46.6,55.6,76.9,77.4,79.2,113.0,115.3,115.5,124.9,130.1(d,J C-F= 8.1Hz), 130.6(d,J C-F= 3.0Hz),136.0,141.9,158.4,159.2,161.5(s,1C),162.4(d,J C-F= 247.2Hz).HRMS(ESI + ) Calculated value C 22 H 25 FN5O(M+H) 394.2043. Measured value 394.2042.

[0309] 4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)-N-(propa-2-in-1-yl)pyrimidine-2-amine(83) Propargylamine (56.0 μL, 0.869 mmol) was added to a mixture of 80 (58.0 mg, 0.145 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 24 hours. Since TLC indicated that the reaction was incomplete, additional propargylamine (112 μL, 1.74 mmol) was added, and stirring was continued for a further 6 days. Additional 3-oxetanamine (48 μL, 0.053 mmol) was added, and stirring was continued for a further 48 hours. The mixture was concentrated under vacuum, and the compound was purified by flash chromatography (Â1 / petroleum ether 1:1) to give a pale orange solid (51.3 mg, 94%) at mp147–155°C. 1 H-NMR (500MHz; CDCl3):δ 2.19-1.20(10H,m),2.24(1H,t,J=2.5Hz),4.28(2H,dd,J=5.8,2.5Hz),4.61-4.59(1H,m),5.63-5.59( 1H,m),6.48(1H,d,J=5.1Hz),7.01-6.96(2H,m),7.46-7.42(2H,m),7.75(1H,s),8.19(1H,d,J=5.1Hz); 13 C NMR(126MHz;CDCl3)δ 25.5,25.9,31.3,34.8,55.6,71.2,81.0,112.9,115.3,115.5,125.0,130.2(d,J C-F =8.0Hz),130.8(d,J C-F =3.3Hz),136.0,142.0,158.4,159.1,161.8,162.4(d,J C-F =247Hz).HRMS(ESI + ) Calculated value C 22 H 23 FN5(M+H) 376.1937. Measured value: 376.1934.

[0310] 2-((4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)amino)ethane-1-ol(84) Ethanolamine (93 μL, 1.56 mmol) was added to a mixture of 80 (0.104 g, 0.261 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 18 hours. TLC showed complete consumption of the sulfone into the more polar compound. The mixture was concentrated under vacuum, and the compound was purified by flash chromatography (siRNA / petroleum ether 8:2) to give a pale yellow solid (79.6 mg, 80%) at mp180–184°C. 1 H NMR(CD3OD,400MHz)δ 1.29-2.15(10H,m),3.56(2H,m),3.74(2H,m),4.58(1H,m),6.37(1H,d,J=4Hz),7.06,(2H,m),7.39(2H,m),8.00(1H,s),8.14(1H,d,J=4Hz); 13 C NMR(CD3OD,101MHz)δ 26.3,26.9 44.7,49.5,57.1,61.9,112.7,116.1,116.35,123.8,126.8,131.3(d,J C-F =8.1Hz),131.7(d,J C-F =3.1Hz),137.4,141.6,159.5,160.0,163.8(d,J C-F =246Hz),164.0.HRMS(ESI + ) Calculated value C 21 H 25 FN5O(M+H) 382.2043. Measured value: 382.2040.

[0311] [C14]

[0312] Benzyl-(4-((cyclopentylimino)methyl)pyrimidine-2-yl)carbamate A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.070 g, 0.274 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol) while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.045 g, 0.328 mmol) were added, followed by cyclopentylamine (54.0 μL, 0.547 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0313] Benzyl(4-(1-(cyclopentyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate A mixture of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.095 g, 0.329 mmol), imine (0.088 g, 0.274 mmol), and a 20% K2CO3 aqueous solution (0.255 mL, 0.329 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 60 hours. The reaction mixture was diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) yielded cyclopentyl carbamate (0.103 mg, 82%).

[0314] 4-(1-(cyclopentyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine Add 20 wt% Pd(OH)2 / C to a solution of cyclopentyl carbamate in 10:1 THF / MeOH. Stir the resulting mixture for 2 hours under a hydrogen atmosphere of 200 psi. Filter the mixture through Celite, concentrate, and purify by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to give a colorless solid.

[0315] Benzyl-(4-((cyclopentylmethylimino)methyl)pyrimidine-2-yl)carbamate A 45% KOH aqueous solution (0.449 g, 8.00 mmol) was added to an ice-cold solution of crude aldehyde 2 (0.147 g, 0.571 mmol) in an HCl aqueous solution (2 ml, 8.00 mmol), while maintaining the temperature below 15°C. To the neutralized solution, CH2Cl2 (5 ml) and K2CO3 (0.095 g, 0.685 mmol) were added, followed by cyclopentylmethylamine (107 μL, 0.113 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 1 1H NMR analysis showed complete consumption of the aldehyde. The crude material was used in the next step without isolation.

[0316] Benzyl(4-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-yl)carbamate Mixtures of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.198 g, 0.5685 mmol), imine (0.193 g, 0.571 mmol), and 20% K2CO3 aqueous solution (0.475 mL, 0.685 mmol) in CH2Cl2 (10 ml) at room temperature are stirred for 72 hours. The reaction mixture is diluted with CH2Cl2, washed with water, dried, filtered, and concentrated. Flash chromatography of the residue (Âde / petroleum ether 3:2) will give cyclopentyl methyl carbamate as a colorless solid.

[0317] 4-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazole-5-yl)pyrimidine-2-amine 20 wt% Pd(OH)2 / C is added to a 10:1 THF / MeOH solution of cyclopentyl methyl carbamate. The resulting mixture is stirred for 2 hours under a hydrogen atmosphere of 200 psi. The mixture is filtered through Celite, concentrated, and purified by flash chromatography (CHCl3 / MeOH / NEt397:2:1) to give a colorless solid.

[0318] 1 W.C.Still,M.Kahn and A.M.Mitra,J.Org.Chem.,1978,43,2923. 2 A.B.Pangborn,M.A.Giardello,R.H.Grubbs,R.K.Rosen and F.J.Timmers,Organometallics,1996,15,1518.

Claims

1. Formula (I): [Formula 1] (In the formula: R1 and R2 are (i) H, C 1〜12 Alkyl, C 2〜6 Alkynyl, C1 alkyl, C6 aryl, C6 aryl, C 3〜6 Cycloalkyl and C 3〜5 heterocyclyl; or (ii) R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl group; R3 is F, Cl, Br, I, CH3, OCH3, OCF2H, OCF3, CO2H, CO2C 1〜10 selected from the group consisting of alkyl; R4 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 1〜12 Alkyl, C 1〜10 Alkyl C6 Aryl, C 1〜6 Alkyl OC 1〜6 Alkyl C6 Aryl, C 0〜6 Alkylheteroaryl, and C 0〜6 wherein each of R1, R2, R3, and R4 is optionally substituted), or a salt, solvate, prodrug, or polymorph thereof.

2. 8. The compound of claim 1, which is not selected from the list of compounds in FIG.

3. The compound of claim 1 or claim 2, wherein R1 is not H.

4. R1 is C 1〜6 4. The compound according to claim 1, wherein the compound is alkyl.

5. R1 is C 1〜3 The alkyl group of claims 1 to 5 is an alkyl group. 4 The compound according to any one of claims 1 to 5.

6. R1 is C 2〜6 The compound of claim 1, which is alkynyl.

7. R1 is C 3〜6 2. The compound of claim 1, which is cycloalkyl.

8. R1 is C 3〜5 2. The compound of claim 1 which is heterocyclyl.

9. Claims 1 to 5, wherein R2 is H. 8 The compound according to any one of claims 1 to 5.

10. The compound of claim 1, wherein R1 and R2 are both the same.

11. 1 to 5, wherein R3 is selected from CH3 and halo. 10 The compound according to any one of claims 1 to 5.

12. R3 is F or Cl. 11 The compound according to claim 1,

13. R4 is C 0〜3 Alkyl C 3〜12 cycloalkyl 12 The compound according to any one of claims 1 to 5.

14. Said C 3〜12 cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 13 The compound according to claim 1,

15. R4 is C 3〜12 cycloalkyl 14 The compound according to any one of claims 1 to 5.

16. R4 is C 1〜12 The alkyl group of claims 1 to 5 is an alkyl group. 12 The compound according to any one of claims 1 to 5.

17. R4 is a methyl, ethyl, propyl, or butyl group. 16 The compound according to claim 1,

18. R4 is C 0〜6 1 to 5, wherein the aryl group is an alkyl heterocyclyl group. 12 The compound according to any one of claims 1 to 5.

19. Formula (Ia): [Case 2] (In the formula: R1 and R2 are (i) H, C 1〜6 Alkyl, C 2〜6 Alkynyl, C6 aryl, and C 3〜5 heterocyclyl; or (ii) R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclyl group; R3 is selected from the group consisting of F, Cl, Br, I, and CH3; R4 is C 0〜3 Alkyl C 3〜12 Cycloalkyl, C 1〜12 Alkyl, and C 0〜6 alkylheterocyclyl; wherein each of R1, R2, R3, and R4 is optionally substituted. The compound according to claim 1, .

20. R1, R2, R3, and R4 are OH, C 1〜6 Alkoxy, halo, amino, mercapto, and C 1〜6 Optionally substituted with one or more groups selected from alkyl, 19 The compound according to any one of claims 1 to 5.

21. Claim 1~ 20 The compound of formula (I) according to any one of or a salt, solvate, prodrug, or polymorph thereof; and a pharma- ceutically acceptable excipient.

22. Claim 1~ 20 or a compound according to any one of claims 21 2. Use of the composition described in claim 1 in the preparation of a medicament for the treatment or prevention of a respiratory disease in a subject.

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